CETP activity inhibitors

ABSTRACT

The present invention provides a CETP activity inhibitor comprising as an active ingredient a compound represented by the formula (I):                    
     wherein R represents a straight chain or branched alkyl group; a straight chain or branched alkenyl group; a lower haloalkyl group; a substituted or unsubstituted cycloalkyl group; a substituted or unsubstituted cycloalkenyl group; a substituted or unsubstituted cycloalkylalkyl group; a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, X 1 , X 2 , X 3 , and X 4  may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower haloalkyl group; a lower alkoxy group; a cyano group; a nitro group; an acyl group; or an aryl group, Y represents —CO— or —SO 2 —, and Z represents a hydrogen atom or a mercapto-protecting group, or a prodrug compound, a pharmaceutically acceptable salt, or hydrate or solvate thereof. The compounds represented by the formula (I) can increase HDL and at the same time decrease LDL through selective inhibition of CETP activity and, therefore, is expected to be useful as a new type of a preventive or therapeutic agent for atherosclerosis or hyperlipidemia.

This application is a 371 of PCT/JP98/00542 filed on Feb. 10, 1998.

TECHNICAL FIELD

This invention relates to a novel CETP activity inhibitor whichcomprises as an active ingredient a compound having abis-(2-aminophenyl) disulfide structure or a 2-amino-phenylthiostructure and more particularly to a pharmaceutical composition fortreating or preventing atherosclerosis or hyperlipidemia. This inventionalso relates to a compound having a bis-(2-aminophenyl) disulfidestructure or a 2-aminophenylthio structure, a prodrug compound, apharmaceutically acceptable salt, hydrates or solvates of thesecompounds.

BACKGROUND ART

From the results of many epidemiological studies, it has been consideredthat there exists certain relation between atherosclerotic diseases andserum lipoprotein. For example, Badimon et al. (J. Clin. Invest. 85,1234-1241 (1990)) reported that not only the prevention of developmentbut also regression of atherosclerotic lesions were observed afterintravenous injection of fractions containing HDL (high densitylipoprotein) and VHDL (very high density lipoprotein) tocholesterol-loaded rabbits. Thus, regarding the relation betweenatherosclerotic diseases and serum lipoproteins, it is expected that HDLand VHDL may have antiatherosclerotic activity.

Recently, it has been elucidated that there are proteins that transferlipids among serum lipoproteins, i.e., CETP (cholesterol ester transferprotein). The presence of CETP was first indicated by Nichols and Smithin 1965 (J. Lipid Res. 6, 206 (1965)). cDNA of the protein was latercloned by Drayna et al. in 1987. Molecular weight of the protein asglycoprotein is 74,000 Da. It is about 58,000 Da after complete removalof sugar chain. cDNA of this protein is composed of 1656 nucleotideresidues and codes for 476 amino acids following signal peptide of 17amino acid residues. Since around 44% of these amino acids arehydrophobic, the protein is highly hydrophobic and liable to beinactivated by oxidation. CETP is synthesized in organs like liver,spleen, adrenal, fat tissue, small intestine, kidney, skeletal muscle,and myocardium. It has been confirmed that CETP is synthesized in cellslike macrophages derived from human monocytes, B lymphocytes, fat cells,small intestinal epithelial cells, CaCo₂ cells, and liver cells (forexample, HepG2 cells derived from human hepatoma cells). In addition tothese tissues, it is present in cerebrospinal fluid and seminal fluid,too. The presence is also confirmed in culture media of neuroblastomaand neuroglioma cells, and in chorioid plexus of sheep.

It has become apparent that CETP participates in metabolism of all thelipoproteins in vivo and plays important roles in reverse transfersystem of cholesterol. It attracted attention as a system that preventsthe accumulation of cholesterol into peripheral cells and functions asprotective mechanism against atherosclerosis. In relation to HDL, whichplays important roles in the reverse transfer system of cholesterol, agreat number of epidemiological studies have shown that a decrease in CE(cholesterol esters) of HDL in blood represents one of the risk factorsfor coronary artery diseases. Activity of CETP differ depending on thespecies of animals and it has become apparent that cholesterol load doesnot bring about atherosclerosis in animals with low CETP activity, whileit is easily produced in animals with high CETP activity. Absence ofCETP results in high HDL-emia+low LDL (low density lipoprotein)-emia andbrings about a state resistant to atherosclerosis. Thus, the importanceof CETP as mediators of transfer of CE in HDL to blood LDL has becomerecognized in addition to the importance of HDL in blood.

Free cholesterol (FC) synthesized in the liver and secreted therefrom istaken up into very low density lipoprotein (VLDL). Next, VLDL ismetabolized in the blood to LDL via intermediate density lipoprotein(IDL) by the action of lipoprotein lipase (LPL) and liver triglyceridelipase (HTGL). LDL is taken up to peripheral cells mediated by LDLreceptor and, thus, FC is supplied to the cells.

Contrary to this flow from the liver to peripheral cells, there existsanother flow of cholesterol from peripheral cells to the liver calledcholesterol reverse transfer system. FC accumulated in peripheral cellsis extracted by HDL, esterified on HDL through the action of LCAT(Lecithin: cholesterol acyltransferase) to form CE, transferred to thehydrophobic core portion of HDL, and HDL becomes matured to globular HDLparticles. CE in HDL is transferred to apoB-containing lipoproteins suchas VLDL, IDL, and LDL by CETP present in the blood. In exchange, TG istransferred to HDL in mole ratio of 1:1. CE that is transferred toapoB-containing lipoprotein is taken up by the liver via LDL receptor onit and, thus, cholesterol is transferred indirectly to the liver. Thereis mechanisms, too, by which HDL becomes CE-rich, apoproteinE-containing HDL by taking up apoprotein E secreted by macrophages andthe like, which is then taken up directly to the liver via LDL receptoror remnant receptor. In another, the liver cells do not take up HDLparticles, but take up selectively only CE in HDL. In still another, HDLparticles are taken up by the liver cells via so-called HDL receptor.

In a state, in which CETP activity is augmented, CE in HDL is decreasedand CE in VLDL, IDL and LDL is increased due to augmentation of CEtransfer from HDL. Increases in uptake of IDL and LDL to the liverresult in down-regulation of LDL receptor and increases in LDL in theblood. In contrast, in a state of CETP deficiency, HDL removescholesterol from peripheral cells with the aid of LCAT, increases itssize gradually and acquires apoE. HDL that becomes apoE-rich is taken upby the liver via LDL receptor of the liver and catabolized. However, asthe operation of this mechanism is not adequate in the human, retentionof large HDL in the blood occurs and, as a result, cholesterol pool inthe liver becomes smaller. LDL receptor becomes up-regulated and LDL isdecreased.

Hence, by selectively inhibiting CETP, it is possible to decrease IDL,VLDL, and LDL that accelerate atherosclerosis and increase HDL thatexhibits inhibitory action. Thus, it is anticipated that hithertonon-existent drugs useful for prevention or therapy of atherosclerosisor hyperlipidemia may be provided.

Very recently there have been reports on chemical compounds that aim atinhibition of such CETP activity.

For example, in Biochemical and Biophysical Research Communications 223,42-47 (1996), dithiodipyridine derivatives and substituted dithiobenzenederivatives are disclosed as compounds capable of inactivating CETPthrough modification of cysteine residues. However, the literatureneither discloses nor suggests the compounds such as those of thepresent invention which have a bis-(2-aminophenyl) disulfide structureor a 2-aminophenylthio structure.

WO95/06626 discloses Wiedendiol-A and Wiedendiol-B as CETP activityinhibitors, but there is no description suggesting the compounds of thepresent invention.

Furthermore, in JP-B-Sho 45-11132, JP-B-Sho 45-2892, JP-B-Sho 45-2891,JP-B-Sho 45-2731, and JP-B-Sho 45-2730, mercaptoanilides substitutedwith higher fatty acids such as o-isostearoylamino thiophenol aredisclosed. However, in these publications, theatherosclerosis-preventing action is only referred to and there is nodescription of test examples that substantiate the action. There is alsono description of CETP inhibitory activity. Nor is there descriptionsuggestive of compounds of the present invention.

There are several reports on the compounds having a bis-(2-aminophenyl)disulfide structure or a 2-aminophenylthio structure similar to those ofthe present application of invention.

For example, WO96/09406 discloses disulfide compounds such as2-acetylaminophenyl disulfide and the like. However, the compounds ofthe publication are the ones that are useful for retrovirus, i.e.,HIV-1, and usefulness as regards inhibitors of CETP activity has notbeen disclosed. There also is no description suggestive of theusefulness.

In JP-A-Hei 8-253454, diphenyl disulfide compounds such as2,2′-di(pyrimidylamino)diphenyldisulfide and the like are disclosed.However, the compounds in this publication are the ones that haveinhibitory action on production of IL-1βand on release of TNFα and thereare no disclosure as regards the usefulness as inhibitors of CETPactivity. There is even no description suggestive of the usefulness.

In JP-A-Hei 2-155937, bis-(acylaminophenyl) disulfide compounds such as2,2 ′-diacetylaminodiphenyl disulfide and the like are disclosed.However, the compounds in this publication relates to the method ofmaking vulcanized rubber filled with carbon black and there are nodisclosure as regards the usefulness as inhibitors of CETP activity.There is also no description suggestive of the usefulness. In the claimsrecited in the publication, C₅-C₁₂ cycloalkyl and cycloalkenyl aredefined as R⁹ and R¹⁰, and as specific examples cyclohexyl andcyclohexenyl are described. However, in the publication no example thatsubstantiates the use of the compound is shown and there is nodescription of the general method of production of the compounds.

JP-A-Hei 2-501772 discloses acylamino phenyl disulfide derivatives suchas o-pivaloylaminophenyl disulfide and the like as intermediates forproduction of pyrazolone photocoupler. However, the invention describedin this publication relates to the photo-element and not suggestive ofthe present invention. This publication also describes 2-cyclohexanecarbonylamino phenylthio group as an example of coupling-off group ofthe coupler, but there is no description of examples that substantiatethe use of the compound.

JP-A-Hei 8-171167 discloses thiophenol derivatives or disulfidederivatives such as 2-acetylamino thiophenol. However, the inventiondescribed in this publication relates to the silver halide emulsion andnot suggestive of the present invention.

In JP-A-Hei 4-233908, disulfide derivatives such asbis-(2-acetoamidephenyl) disulfide and the like are disclosed. However,the compounds of this publication is disclosed as chain transfer agentsand, thus, the publication does not suggest the present invention. Asspecific examples of R₃ in X,Y, a cyclohexyl group is disclosed, but theexample substantiating the use and the general method of production arenot described.

JP-A-Sho 63-157150 discloses amidophenyl disulfide derivatives such aso-pivalamidophenyl disulfide and the like as stabilizers. However, theinvention of this publication relates to photo-element and is notsuggestive of the present invention. In the claim recited in thispublication, a cycloalkyl group is defined as R in the substituents V orY of the stabilizer compounds, but the example substantiating the useand the general method of production are not described.

Bis-(amidophenyl) disulfide derivatives are also disclosed in JP-A-Hei8-59900, JP-A-Hei 7-258472, JP-A-Hei 7-224028, JP-A-Hei 7-49554,JP-A-Hei 6-19037, JP-A-Hei 6-19024, JP-A-Hei 3-226750, JP-A-Hei2-284146, JP-A-Hei 2-23338, JP-A-Hei 1-321432, JP-A-Hei 1-278543, andJP-B-Sho 47-357786. However, none of them discloses usefulness asinhibitors of CETP activity and there is no description suggestive ofthe usefulness.

DISCLOSURE OF THE INVENTION

As described above, the present inventors studied ardently in order toprovide the compounds that selectively inhibit CETP activity and, as aresult, found compounds useful as novel preventive or therapeutic agentsof atherosclerosis or hyperlipidemia with new action mechanism whichcould increase HDL and at the same time decrease LDL, thereby completingthe present invention.

The present invention relates to the compounds and medicaments as shownin the following (1) to (19) which have CETP activity inhibitory effect.

(1) A CETP activity inhibitor comprising as an active ingredient acompound represented by the formula (I):

 wherein

R represents

a straight chain or branched C₁₋₁₀ alkyl group;

a straight chain or branched C₂₋₁₀ alkenyl group;

a halo-C₁₋₄ lower alkyl group;

a substituted or unsubstituted C₃₋₁₀ cycloalkyl group;

a substituted or unsubstituted C₅₋₈ cycloalkenyl group;

a substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group;

a substituted or unsubstituted aryl group;

a substituted or unsubstituted aralkyl group; or

a substituted or unsubstituted 5- or 6-membered heterocyclic grouphaving 1-3 nitrogen, oxygen or sulfur atoms,

X₁, X₂, X₃, and X₄ may be the same or different and represents

a hydrogen atom;

a halogen atom;

a C₁₋₄ lower alkyl group;

a halo-C₁₋₄ lower alkyl group;

a C₁₋₄ lower alkoxy group;

a cyano group;

a nitro group;

an acyl group; or

an aryl group,

Y represents

—CO—; or

—S₂, and

Z represents

a hydrogen atom; or

a mercapto-protecting group,

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(2) A CETP activity inhibitor comprising as an active ingredient thecompound described in the above (1), wherein

R represents

a straight chain or branched C₁₋₁₀ alkyl group;

a straight chain or branched C₂₋₁₀ alkenyl group;

a halo-C₁₋₄ lower alkyl group substituted with 1-3 halogen atomsselected from fluorine, chlorine, and bromine;

a C₃₋₁₀ cycloalkyl group, a C₅₋₈ cycloalkenyl group, or a C₃₋₁₀cycloalkyl C₁₋₁₀ alkyl group, each of which may have 1-4 substituentsselected from the group consisting of

a straight chain or branched C₁₋₁₀ alkyl group,

a straight chain or branched C₂₋₁₀ alkenyl group,

a C₃₋₁₀ cycloalkyl group,

a C₅₋₈ cycloalkenyl group,

a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group,

an aryl group selected from phenyl, biphenyl, and naphthyl,

an oxo group, and

an aralkyl group having an aryl group selected from phenyl, biphenyl,and naphthyl; or

an aryl, aralkyl, or 5- or 6-membered heterocyclic group with 1-3nitrogen, oxygen or sulfur atoms, each of which may have 1-4substituents selected from the group consisting of

a straight chain or branched C₁₋₁₀ alkyl group,

a straight chain or branched C₂₋₁₀ alkenyl group,

a halogen atom selected from fluorine, chlorine, and bromine,

a nitro group, and

a halo-C₁₋₄ lower alkyl group having a halogen atom selected fromfluorine, chlorine, and bromine;

Z represents

a hydrogen atom;

a mercapto-protecting group selected from the group consisting of

a C₁₋₄ lower alkoxymethyl group,

a C₁₋₄ lower alkylthiomethyl group,

an aralkyloxymethyl group having an aryl group selected from phenyl,biphenyl, and naphthyl,

an aralkylthiomethyl group having an aryl group selected from phenyl,biphenyl, and naphthyl,

a C₃₋₁₀ cycloalkyloxymethyl group,

a C₅₋₈ cycloalkenyloxymethyl group,

a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkoxymethyl group,

an aryloxymethyl group having an aryl group selected from phenyl,biphenyl, and naphthyl,

an arylthiomethyl group having an aryl group selected from phenyl,biphenyl, and naphthyl,

an acyl group,

an acyloxy group,

an aminocarbonyloxymethyl group,

a thiocarbonyl group, and

a thio group,

 a prodrug compound thereof, a pharmaceutically acceptable salt,hydrate, or solvate thereof.

(3) A CETP activity inhibitor comprising as an active ingredient thecompound as described in the above (2), which is represented by theformula (I-1):

 wherein

R, X₁, X₂, X₃, X₄, and Y are the same as in the above (2) and

Z₁ represents

a hydrogen atom;

a group represented by the formula

wherein R, X₁, X₂, X₃, X₄, and Y are the same as described above;

—Y₁R₁,

wherein

Y₁ represents

—CO—; or

—CS—, and

R₁ represents

a substituted or unsubstituted straight chain or branched C₁₋₁₀ alkylgroup;

a C₁₋₄ lower alkoxy group;

a C₁₋₄ lower alkylthio group;

a substituted or unsubstituted amino group;

a substituted or unsubstituted ureido group;

a substituted or unsubstituted C₃₋₁₀ cycloalkyl group;

a substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group;

a substituted or unsubstituted aryl group;

a substituted or unsubstituted aralkyl group;

a substituted or unsubstituted arylalkenyl group;

a substituted or unsubstituted arylthio group;

a substituted or unsubstituted 5- or 6-membered heterocyclic grouphaving 1-3 nitrogen, oxygen, or sulfur atoms; or

a substituted or unsubstituted 5- or 6-membered heteroarylalkyl group;or

—S—R₂,

wherein R₂ represents

a substituted or unsubstituted C₁₋₄ lower alkyl group; or

a substituted or unsubstituted aryl group,

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(4) A CETP activity inhibitor comprising as an active ingredient thecompound as described in the above (3), wherein

R₁ represents

a straight chain or branched C₁₋₁₀ alkyl group which may have 1-3substituents selected from the group consisting of

a halogen atom selected from fluorine, chlorine, and bromine,

a C₁₋₄ lower alkoxy group,

an amino group that may be substituted with a C₁₋₄ lower alkyl, acyl, orhydroxyl group,

a C₁₋₄ lower alkylthio group,

a carbamoyl group,

a hydroxyl group,

an acyl group,

an acyloxy group having an acyl group,

a carboxyl group, and

an aryloxy group that may be substituted with a halogen atom selectedfrom fluorine, chlorine, and bromine;

a C₁₋₄ lower alkoxy group;

a C₁₋₄ lower alkylthio group;

an amino or ureido group that may have 1-2 substituents selected fromthe group consisting of

a C₁₋₄ lower alkyl group,

a hydroxyl group,

an acyl group, and

an aryl group that may be substituted with a lower C₁₋₄ alkoxy group;

a C₃₋₁₀ cycloalkyl or C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group that may havesubstituents selected from the group consisting of

a straight or branched C₁₋₁₀ alkyl group,

a C₃₋₁₀ cycloalkyl group,

a C₅₋₈ cycloalkenyl group,

an aryl group,

an amino group,

a C₁₋₄ lower alkylamino group having a C₁₋₄ lower alkyl group, and

an acylamino group having an acyl group;

an aryl group, an aralkyl group, an arylalkenyl group, or an arylthiogroup, each of which may have 1-4 substituents selected from the groupconsisting of

a C₁₋₁₀ alkyl group,

a halogen atom selected from fluorine, chlorine, and bromine,

a nitro group,

a hydroxyl group,

a C₁₋₄ lower alkoxy group,

a C₁₋₄ lower alkylthio group,

an acyl group,

a halo-C₁₋₄ lower alkyl group having a halogen atom selected fromfluorine, chlorine, and bromine, and

an amino group that may be substituted with a C₁₋₄ lower alkyl or acylgroup;

a 5- or 6-membered heterocyclic group having 1-3 nitrogen, oxygen orsulfur atoms or a 5- or 6-membered heteroarylalkyl group that may have1-4 substituents selected from the group consisting of

a straight chain or branched C₁₋₁₀ alkyl group,

a halogen atom selected from fluorine, chlorine, and bromine,

an acyl group,

an oxo group, and

an halo-C₁₋₄ lower alkyl group having a halogen atom selected fromfluorine, chlorine, and bromine; and

R₂ represents

a C₁₋₄ lower alkyl group that may have 1-3 substituents selected fromthe group consisting of

a C₁₋₄ lower alkoxy groups,

an amino group that may be substituted with a C₁₋₄ lower alkyl or acylgroup,

a C₁₋₄ lower alkylthio group,

a carbamoyl group,

a hydroxyl group,

a carboxyl group,

an acyl group, and

a 5- or 6-membered heterocyclic group having 1-3 nitrogen, oxygen, orsulfur atoms; or

an aryl group that may have 1-4 substituents selected from the groupconsisting of

a C₁₋₄ lower alkyl group,

a halogen atom selected from fluorine, chlorine, and bromine,

a nitro group,

a hydroxyl group,

a C₁₋₄ lower alkoxy group,

a C₁₋₄ lower alkylthio group,

an acyl group,

an amino group that may be substituted with a C₁₋₄ lower alkyl or acylgroup, and

a halo-C₁₋₄ lower alkyl group having a halogen atom selected fromfluorine, chlorine, and bromine,

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(5) A CETP activity inhibitor comprising as an active ingredient thecompound as described in the above (1), which is selected from the groupconsisting of

bis-[2-(pivaloylamino)phenyl]disulfide;

bis-[2-(2-propylpentanoylamino)phenyl]disulfide;

bis-[2-(1-methylcyclohexanecarbonylamino)phenyl]disulfide;

bis-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]disulfide;

bis-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]disulfide;

N-(2-mercaptophenyl)-2,2-dimethylpropionamide;

N-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-methylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;

N-(2-mercaptophenyl)-1-isopropylcyclohexanecarboxamide;

N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;

N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;

N-(2-mercapto-5-methylphenyl)-1-isopentylcyclohexanecarboxamide;

N-(2-mercapto-4-methylphenyl)-1-isopentylcyclohexanecarboxamide;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thioacetate;

S-[2-(1-methylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(pivaloylamino)phenyl]phenylthioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]phenoxythioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;

S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;

S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;

O-methyl S-[2-(1-isopentylcyclohexanecarbonylamino)phenylmonothiocarbonate;

S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyl dithiocarbonate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;

S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;

S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]disulfide;

2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonyl amino)phenyldisulfide;

N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;

S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;

bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;

N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;

S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;

S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;and

S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]1-acetylpiperidine-4-thiocarboxylate,

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(6) A prophylactic or therapeutic agent for hyperlipidemia comprising asan active ingredient the compound as described in the above in (1)-(5),a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(7) A prophylactic or therapeutic agent for atherosclerosis comprisingas an active ingredient the compound as described in the above in(1)-(5), a prodrug compound, a pharmaceutically acceptable salt, orhydrate or solvate thereof.

(8) A Compound represented by the formula (I-2):

 wherein

R′ represents

a substituted or unsubstituted C₃₋₁₀ cycloalkyl group or

a substituted or unsubstituted C₅₋₈ cycloalkenyl group;

X₁, X₂, X₃ , and X₄ are as in the above (1); and

Z₁′ represents

a hydrogen atom;

a group represented by the formula:

wherein R′, X₁, X₂, X₃, and X₄ are as described above;

—Y₁R₁,

wherein Y₁ and R₁ are the same as in the above (3) or

—S—R₂,

wherein R₂ is the same as in the above (3),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(9) A compound as described above in (8), which is represented by theformula (I-3):

 wherein

R″ represents

a 1-substituted-C₃₋₁₀ cycloalkyl group or

a 1-substituted-C₅₋₈ cycloalkenyl group;

X₁, X₂, X₃, and X₄ are the same as in the above (1); and

Z₁″ represents

a hydrogen atoms;

a group represented by the formula:

wherein R″, X₁, X₂, X₃, and X₄ are as described above;

—Y₁R₁,

wherein Y₁ and R₁ are the same as in the above (3); or

—S—R₂,

wherein R₂ is the same as in the above (3),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(10) A compound as described in the above (8), which is represented bythe formula (II):

wherein R′, X₁, X₂, X₃, and X₄ are the same as in the above (8),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(11) A compound as described in the above (9), which is represented byformula (II-1):

wherein R″, X₁, X₂, X₃, and X₄ are the same as in the above (9),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(12) A compound as described in the above (8), which represented by theformula (III):

wherein R′, X₁, X₂, X₃, and X₄ are the same as in the above (8),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(13) A compound as described in the above (9), which is represented byformula (III-1):

wherein R″, X₁, X₂, X₃, and X₄ are the same as in the above (9),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(14) A compound as described in the above (8), which is represented byformula (IV):

wherein R′, X₁, X₂, X₃, X₄, Y₁, and R₁ are the same as in the above (8),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(15) A compound as described in the above (9), which is represented byformula (IV-1):

wherein R″, X₁, X₂, X₃, X₄, Y₁, and R₁ are the same as in the above (9),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(16) A compound as described in the above (8), which is represented byformula (V):

wherein R′, X₁, X₂, X₃, X₄, and R₂ are the same as in the above (8),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(17) A compound as described in the above (9), which is represented byformula (V-1):

wherein R″, X₁, X₂, X₃, X₄, and R₂ are the same as in the above (9),

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(18) A compound as described in the above (8), which is selected fromthe group consisting of

bis-[2-(1-methylcyclohexanecarbonylamino)phenyl]disulfide;

bis-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]disulfide;

bis-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]disulfide;

N-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-methylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;

N-(2-mercaptophenyl)-1-isopropylcyclohexanecarboxamide;

N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;

N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;

N-(2-mercapto-5-methylphenyl)-1-isopentylcyclohexanecarboxamide;

N-(2-mercapto-4-methylphenyl)-1-isopentylcyclohexanecarboxamide;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thioacetate;

S-[2-(1-methylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]phenoxythioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;

S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylpropionate;

S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;

S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;

O-methylS-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]monothiocarbonate;

S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyldithiocarbonate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;

S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropioate;

S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;

S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]disulfide;

2-tetrahydrofurylmethyl2-(1-isopentylcyclohexanecarbonylamino)phenyldisulfide;

N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;

S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;

bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;

N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;

S-[2-(1-isobutylcyclohexanecarbonylamino]phenyl]2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylpropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;

S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;and

S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]1-acetylpiperidine-4-thiocarboxylate,

 a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(19) A phamaceutical composition comprising as an active ingredient thecompound as described in the above (8)-(18), a prodrug compound, apharmaceutically acceptable salt, hydrate, or solvate thereof.

(20) Use of the compound represented by the above formula (I), a prodrugcompound, a pharmaceutically acceptable salt, hydrate, or solvatethereof, for production of a CETP activity inhibitor.

(21) Use of the compound represented by the above formula (I), a prodrugcompound, a pharmaceutically acceptable salt, hydrate, or solvatethereof, for production of a prophylactic or therapeutic agent forhyperlipidemia.

(22) Use of the compound represented by the above formula (I), a prodrugcompound, a pharmaceutically acceptable salt, hydrate, or solvatethereof, for production of a prophylactic or therapeutic agent foratherosclerosis.

(23) A method for inhibition of CETP activity comprising administeringto patients the compound represented by the above formula (I), a prodrugcompound, a pharmaceutically acceptable salt, hydrate, or solvatethereof.

(24) A method for prevention or therapy of hyperlipidemia comprisingadministering to patients the compound represented by the above formula(I), a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

(25) A method for prevention or therapy of atherosclerosis comprisingadministering to patients the compound represented by the above formula(I), a prodrug compound, a pharmaceutically acceptable salt, or hydrate,or solvate thereof.

The term “straight chain or branched C₁₋₁₀ alkyl group” used hereinmeans an alkyl group having 1-10 carbon atoms which may be straight orbranched. Specific examples thereof include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl, 1-ethylbutyl, 2-ethylbutyl, 1-propylbutyl,1,1-dimethylbutyl, 1-isobutyl-3-methylbutyl, 1-ethylpentyl,1-propylpentyl, 1-isobutylpentyl, 2-ethylpentyl, 2-isopropylpentyl,2-tert-butylpentyl, 3-ethylpentyl, 3-isopropylpentyl, 4-methylpentyl,1,4-dimethylpentyl, 2,4-dimethylpentyl, 1-ethyl-4-methylpentyl, hexyl,1-ethylhexyl, 1-propylhexyl, 2-ethylhexyl, 2-isopropylhexyl,2-tert-butylhexyl, 3-ethylhexyl, 3-isopropylhexyl, 3-tert-butylhexyl,4-ethylhexyl, 5-methylhexyl, heptyl, 1-ethylheptyl, 1-isopropylheptyl,2-ethylheptyl, 2-isopropylheptyl, 3-propylheptyl, 4-propylheptyl,5-ethylheptyl, 6-methylheptyl, octyl, 1-ethyloctyl, 2-ethyloctyl, nonyl,1-methylnonyl, 2-methylnonyl, decyl, and the like groups. A straightchain or branched alkyl group having 1-8 carbon atoms is preferred.

The term “C₁₋₄ lower alkyl group” used herein means an alkyl grouphaving 1-4 carbon atoms, and specifically includes methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the likegroups.

The term “straight chain or branched C₂₋₁₀ alkenyl group” means analkenyl group having 2-10 carbon atoms with at least one or more doublebonds, which may be straight or branched. Specific examples thereofinclude allyl, vinyl, isopropenyl, 1-propenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-methyl-1-butenyl, crotyl, 1-methyl-3-butenyl,3-methyl-2-butenyl, 1,3-dimethyl-2-butenyl, 1-pentenyl,1-methyl-2-pentenyl, 1-ethyl-3-pentenyl, 4-pentenyl, 1,3-pentadienyl,2,4-pentadienyl, 1-hexenyl, 1-methyl-2-hexenyl, 3-hexenyl, 4-hexenyl,1-butyl-5-hexenyl, 1,3-hexadienyl, 2,4-hexadienyl, 1-heptenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl,1,3-heptadienyl, 2,4-heptadienyl, 1-octenyl, 2-octenyl, 3-octenyl,4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl,3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl,9-decenyl, and the like groups. An alkenyl group having 2-8 carbonatoms, which may be straight or branched, is preferred.

The term “halogen atom” means fluorine, chlorine, and bromine atoms.

The term “halo-C₁₋₄ alkyl group” means the above-described C₁₋₄ loweralkyl group substituted with 1-3 halogens, which may be the same ordifferent. Specific examples thereof include fluoromethyl, chloromethyl,bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl,trichloromethyl, chloroethyl, difluoroethyl, trifluoroethyl,pentachloroethyl, bromopropyl, dichloropropyl, trifluorobutyl, and thelike groups. Trifluoromethyl and chloroethyl are preferred.

The term “C₁₋₄ lower alkoxy group” means the alkoxy group containing theC₁₋₄ lower alkyl group as described above. Examples thereof includemethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, and the like groups.

The term “C₁₋₄ lower alkylthio group” means the alkylthio groupcontaining the C₁₋₄ lower alkyl group as described above. Examplesthereof include methylthio, ethylthio, propylthio, isopropylthio,butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the likegroups.

The term “C₃₋₁₀ cycloalkyl group” means a cycloalkyl group having 3-10carbon atoms, which may be monocyclic or polycyclic. Examples thereofinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, octahydroindenyl, decahydronaphthyl, bicyclo[2.2.1]heptyl,adamantyl, and the like groups. Preferred are those having 5-7 carbonatoms, including cyclopentyl, cyclohexyl, and cycloheptyl.

The term “C₅₋₈ cycloalkenyl group” means a cycloalkenyl group having 5-8carbon atoms with one or more double bonds on the ring. Examples thereofinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl,and the like groups. Preferred are those with 5-7 carbon atoms,including cyclopentenyl, cyclohexenyl, and cycloheptenyl.

The term “C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group” means the above-describedstraight chain or branched C₁₋₁₀ alkyl group substituted with theabove-described C₃₋₁₀ cycloalkyl group. Specific examples thereofinclude cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,cyclohexyl cyclopentylmethyl, dicyclohexylmethyl, 1-cyclopentylethyl,1-cyclohexylethyl, 2-cyclopropylethyl, 2-cyclopentylethyl,2-cyclohexylethyl, 2-cycloheptylethyl, 1-cyclohexyl-1-methylethyl,1-cyclohexylpropyl, 2-cyclopentylpropyl, 3-cyclobutylpropyl,3-cyclopentylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl,1-cyclopropyl-1-methylpropyl, 1-cyclohexyl-2-methylpropyl,1-cyclopentylbutyl, 1-cyclohexylbutyl, 3-cyclohexylbutyl,4-cyclopropylbutyl, 4-cyclobutylbutyl, 4-cyclopentylbutyl,1-cyclohexyl-1-methylbutyl, 1-cyclopentyl-2-ethylbutyl,1-cyclohexyl-3-methylbutyl, 1-cyclopentylpentyl, 1-cyclohexylpentyl,1-cyclohexylmethylpentyl, 2-cyclohexylpentyl, 2-cyclohexylmethylpentyl,3-cyclopentylpentyl, 1-cyclohexyl-4-methylpentyl, 5-cyclopentylpentyl,1-cyclopentylhexyl, 1-cyclohexylhexyl, 1-cyclopentylmethylhexyl,2-cyclopentylhexyl, 2-cyclopropylethylhexyl, 3-cyclopentylhexyl,1-cyclohexylheptyl, 1-cyclopentyl-1-methylheptyl,1-cyclohexyl-1,6-dimethylheptyl, 1-cycloheptyloctyl, 2-cyclopentyloctyl,3-cyclohexyloctyl, 2-cyclopentylmethyloctyl, 1-cyclopentylnonyl,1-cyclohexylnonyl, 3-cyclopropylnonyl, 1-cyclopentyldecyl,1-cyclohexylundecyl, 1-cyclopentyltridecyl, 2-cyclohexyltridecyl, andthe like groups.

The “aryl group” includes phenyl, naphthyl, anthryl, phenanthryl,biphenyl, and the like groups. Phenyl, naphthyl, and biphenyl groups arepreferred.

The “aralkyl group” means the above-described C₁₋₄ lower alkyl groupsubstituted with one or more aryl groups as described above. Examplesthereof include benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl,2-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl,4-biphenylmethyl, 3-(4-biphenyl) propyl, and the like groups.

The “arylalkenyl group” means an alkenyl group having 2-4 carbon atomssubstituted with the above-described aryl group. Examples thereofinclude 2-phenylvinyl, 3-phenyl-2-propenyl,3-phenyl-2-methyl-2-propenyl, 4-phenyl-3-butenyl, 2-(1-naphthyl)vinyl,2-(2-naphthyl)vinyl, 2-(4-biphenyl)vinyl, and the like groups.

The “arylthio group” means an arylthio group containing theabove-described aryl group and specifically include phenylthio,naphthylthio, and the like groups.

The “heterocyclic ring group” means 5- and 6-membered aromatic ornon-aromatic heterocyclic ring groups containing at least one or more,specifically 1-4, preferably 1-3, hetero atoms selected from nitrogen,oxygen, and sulfur atoms. Specific examples thereof include aromaticheterocyclic rings such as thiatriazolyl, tetrazolyl, dithiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, pyrazolyl, pyrrolyl,furyl, thienyl, tetrazinyl, triazinyl, pyrazinyl, pyridazinyl,pyrimidinyl, pyridyl, or the like groups and non-aromatic heterocyclicrings such as dioxoranyl, pyrrolidinyl, tetrahydrofuryl,tetrahydrothienyl, dithiadiazinyl, thiadiazinyl, morpholino,morpholinyl, oxazinyl, thiazinyl, piperazinyl, piperidyl, piperidino,pyranyl, thiopyranyl, or the like groups. Preferable groups are aromaticheterocyclic (heteroaryl) groups including furyl, thienyl, pyrrolyl,pyridyl, and the like and non-aromatic heterocyclic groups containing atleast one nitrogen atom, including pyrrolidinyl, tetrahydrofuryl,piperazinyl, piperidyl, piperidino, and the like groups.

The “heteroarylalkyl group” means the above-described C₁₋₄ lower alkylgroup substituted with the above-described 5- or 6-membered aromaticheterocyclic (heteroaryl) group and specifically include2-thienylmethyl, 2-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl,2-thienyl-2-ethyl, 3-furyl-1-ethyl, 2-pyridyl-3-propyl, and the likegroups.

The “acyl group” specifically includes formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl,propioloyl, metacryloyl, crotonoyl, benzoyl, naphthoyl, toluoyl,hydroatropoyl, atropoyl, cinnamoyl, furoyl, thenoyl, nicotinoyl,isonicotinoyl, glucoloyl, lactoyl, glyceroyl, tropoyl, benzyloyl,salicyloyl, anisoyl, vaniloyl, veratoroyl, piperoniroyl, protocatechoyl,galloyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl, 1-methyl cyclohexanecarbonyl,1-isopentylcyclopentanecarbonyl, 1-isopentyl cyclohexanecarbonyl,tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl,2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl, and the likegroups. Preferred are acetyl, tert-butoxycarbonyl, benzoyl,1-methylcyclohexanecarbonyl, 1-isopentylcyclopentanecarbonyl,1-isopentylcyclohexanecarbonyl, and2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl.

The term “substituted or unsubstituted” of the “substituted orunsubstituted C₃₋₁₀ cycloalkyl group”, the “substituted or unsubstitutedC₅₋₈ cycloalkenyl group”, and the “substituted or unsubstituted C₃₋₁₀cycloalkyl C₁₋₁₀ alkyl group” described for R, R₁, and the like meansthat the group may be substituted with 1-4 substituents which may be thesame or different and any position may be arbitrarily substitutedwithout any limitation. Specific examples of these groups are theabove-described straight chain or branched C₁₋₁₀ alkyl group; theabove-described straight chain or branched C₂₋₁₀ alkenyl group; theabove-described C₃₋₁₀ cycloalkyl group; the above-described C₁₋₁₀cycloalkenyl group; the above-described C₃₋₁₀ cycloalkyl C₁₋₁₀ alkylgroup; the above-described aryl group; an amino group; a C₁₋₄ loweralkylamino group such as methylamino, ethylamino, or the like groups; anacylamino group such as acetylamino, propionylamino, benzylamino, or thelike groups; an oxo group; the above-described aralkyl group; theabove-described arylalkenyl group, and the like.

The above substituents are recommended as substituents for R. Amongthese, preferred for R₁ are the above-described straight chain orbranched C₁₋₁₀ alkyl group, the above-described C₃₋₁₀ cycloalkyl group,the above-described C₅₋₈ cycloalkenyl group, the above-described arylgroup, and the above-described amino group.

The term “substituted or unsubstituted” of the “substituted orunsubstituted aryl group”, the “15- or 6-membered heterocyclic groupcontaining 1-3 nitrogen, oxygen, or sulfur atoms”, the “substituted orunsubstituted aralkyl group”, the “substituted or unsubstitutedarylalkenyl group”, the “substituted or unsubstituted arylthio group”,and the “substituted or unsubstituted 5- or 6-membered heteroarylalkylgroup” described with respect to R, R₁, and the like means that thegroups may be substituted with 1-4, preferably 1-3, substituents whichmay be the same or different and any position may be arbitrarilysubstituted without particular restriction. Examples of these groupsinclude the above-described straight chain or branched C₁₋₁₀ alkylgroup, preferably a straight chain or branched C₁₋₆ aralkyl group; theabove-described straight chain or branched C₂₋₁₀ alkenyl group,preferably a straight chain or branched C₂₋₆ alkenyl group; theabove-described halogen atom; a nitro group; the above-described aminogroup that may be substituted with the above-described C₁₋₄ lower alkylgroup or the above-described acyl group; a hydroxyl group; theabove-described C₁₋₄ lower alkoxy group; the above-described C₁₋₄ loweralkylthio group; the above-described halo-C₁₋₄ lower alkyl group; theabove-described acyl group; an oxo group, and the like.

The above substituents are recommended as substituents mainly for R₁.Among these, preferred for R the above-described straight chain orbranched C₁₋₆ alkyl group, the above-described halogen atom, and a nitrogroup.

The “substituted or unsubstituted” of the “substituted or unsubstitutedstraight chain or branched C₁₋₁₀ alkyl group” described for R₁ and thelike means that the group may be substituted with 1-3 substituents whichmay be the same or different and any position may be arbitrarilysubstituted without particular restriction. Examples of these groups arethe above-described C₁₋₄ lower alkoxy group; the above-described C₁₋₄lower alkyl group; the above-described amino group that may besubstituted with an acyl or hydroxyl group; the above-described lowerC₁₋₄ alkylthio group; a carbamoyl group; a hydroxyl group; theabove-described halogen atom; the above-described acyloxy groupcontaining an acyl group; a carboxyl group; the above-described acylgroup; the above-described aryloxy group containing an aryl group thatmay be substituted; and the like.

The “substituted or unsubstituted” of the “C₁₋₄ lower alkyl group”described with respect to R₂ and the like means that the group may besubstituted with 1-3 substituents which may be the same or different andany position may be arbitrarily substituted without particularrestriction. Examples of the group include the above-described C₁₋₄lower alkoxy group; the above-described amino group that may besubstituted with the above-described C₁₋₄ lower alkyl group or theabove-described acyl group; the above-described C₁₋₄ lower alkylthiogroup; a carbamoyl group; a hydroxyl group; a carboxyl group; theabove-described acyl group; the above-described heterocyclic group(particularly aromatic heterocyclic groups such as thienyl ornon-aromatic heterocyclic group such as tetrahydrofuryl); and the like.

The term “substituted or unsubstituted” of the “substituted orunsubstituted amino group” and the “substituted or unsubstituted ureidogroup” described with respect to R₁ means that the groups may besubstituted with one or more, preferably 1-2, substituents which may bethe same or different and any position may be arbitrarily substitutedwithout particular restriction. Examples of these groups are theabove-described C₁₋₄ lower alkyl group; a hydroxyl group; theabove-described acyl group; the above-described aryl group which may besubstituted with the above-described C₁₋₄ lower alkoxy group; and thelike.

The “mercapto-protecting group” described with respect to Z meanscommonly used mercapto protecting groups. Any organic residues that canbe dissociated in vivo may be used without particular restriction. Itmay form a disulfide structure, that is dimer. Examples thereof includeC₁₋₄ lower alkoxymethyl; C₁₋₄ lower alkylthiomethyl; aralkyloxymethyl;aralkylthiomethyl; C₃₋₁₀ cycloalkyloxymethyl; C₅₋₈cycloalkenyloxymethyl; C₃₋₁₀ cycloalkyl C₁₋₁₀ alkoxymethyl;aryloxymethyl; arylthiomethyl; acyl; acyloxy; aminocarbonyloxymethyl;thiocarbonyl; and thio groups. Specific examples thereof include a C₁₋₄lower alkoxymethyl group with the above-described C₁₋₄ lower alkoxygroup; a C₁₋₄ lower alkylthiomethyl group with the above-described C₁₋₄lower alkylthio group; an aralkyloxymethyl group with theabove-described aralkyl group; an aralkylthiomethyl group with theabove-described aralkyl group; a C₃₋₁₀ cycloalkyloxymethyl group withthe above-described C₃₋₁₀ cycloalkyl group; a C₅₋₈ cycloalkenyloxymethylgroup with the above-described C₅₋₈ cycloalkenyl group; a C₃₋₁₀cycloalkyl C₁₋₁₀ alkoxymethyl group with the above-described C₃₋₁₀cycloalkyl C₁₋₁₀ alkyl group; an aryloxymethyl group with theabove-described aryl group; an arylthiomethyl group with theabove-described arylthio group; an acyl group containing theabove-described substituted or unsubstituted straight chain or branchedC₁₋₁₀ alkyl group, the above-described halo-C₁₋₄ lower alkyl group, theabove-described C₁₋₄ lower alkoxy group, the above-described C₁₋₄ loweralkylthio group, the above-described substituted or unsubstituted aminogroup, the above-described substituted or unsubstituted ureido group,the above-described substituted or unsubstituted C₃₋₁₀ cycloalkyl group,the above-described substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀alkyl group, the above-described substituted or unsubstituted arylgroup, the above-described substituted or unsubstituted aralkyl group,the above-described substituted or unsubstituted arylalkenyl group, theabove-described substituted or unsubstituted arylthio group, theabove-described substituted or unsubstituted 5- or 6-memberedheterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or theabove-described substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group; an acyloxy group containing the above-describedsubstituted or unsubstituted straight chain or branched C₁₋₁₀ alkylgroup, the above-described halo-C₁₋₄ lower alkyl group, theabove-described C₁₋₄ lower alkoxy group, the above-described C₁₋₄ loweralkylthio group, the above-described substituted or unsubstituted aminogroup, the above-described substituted or unsubstituted ureido group,the above-described substituted or unsubstituted C₃₋₁₀ cycloalkyl group,the above-described substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀alkyl group, the above-described substituted or unsubstituted arylgroup, the above-described substituted or unsubstituted aralkyl group,the above-described substituted or unsubstituted arylalkenyl group, theabove-described substituted or unsubstituted arylthio group, theabove-described substituted or unsubstituted 5- or 6-memberedheterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or theabove-described substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group; an aminocarbonyloxymethyl group that may besubstituted with the above-described substituted or unsubstitutedstraight chain or branched C₁₋₁₀ alkyl group, the above-describedhalo-C₁₋₄ alkyl group, the above-described C₁₋₄ lower alkoxy group, theabove-described C₁₋₄ lower alkylthio group, the above-describedsubstituted or unsubstituted C₃₋₁₀ cycloalkyl group, the above-describedsubstituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group, theabove-described substituted or unsubstituted aryl group, theabove-described substituted or unsubstituted aralkyl group, theabove-described substituted or unsubstituted arylalkenyl group, theabove-described substituted or unsubstituted 5- or 6-memberedheterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or theabove-described substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group; a thiocarbonyl group containing theabove-described substituted or unsubstituted straight chain or branchedC₁₋₁₀ alkyl group, the above-described halo-C₁₋₄ lower alkyl group, theabove-described C₁₋₄ lower alkoxy group, the above-described C₁₋₄ loweralkylthio group, the above-described substituted or unsubstituted aminogroup, the above-described substituted or unsubstituted ureido group,the above-described substituted or unsubstituted C₃₋₁₀ cycloalkyl group,the above-described substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀alkyl group, the above-described substituted or unsubstituted arylgroup, the above-described substituted or unsubstituted aralkyl group,the above-described substituted or unsubstituted arylalkenyl group, theabove-described substituted or unsubstituted arylthio group, theabove-described substituted or unsubstituted 5- or 6-memberedheterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or theabove-described substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group; and a thio group containing the above-describedsubstituted or unsubstituted C₁₋₄ lower alkyl or aryl group.

More specifically, preferred as the “straight chain or branched C₁₋₁₀alkyl group” for R are methyl, ethyl, isopropyl, butyl, isobutyl,tert-butyl, heptyl, 1-propylbutyl, and 1-isobutyl-3-methylbutyl.

The “straight chain or branched C₂₋₁₀ alkenyl group” referred to as Rare preferably allyl, vinyl, isopropenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-methyl-1-butenyl, crotyl, 1,3-dimethyl-2-butenyl,1-pentenyl, and 1-methyl-2-pentenyl.

The “halo-C₁₋₄ lower alkyl group” for R means a C₁₋₄ lower alkyl group,particularly preferably a methyl group, substituted with theabove-described halogen atom, particularly preferably fluorine andchlorine, with being a trifluoromethyl group preferred.

The “substituted or unsubstituted C₃₋₁₀ cycloalkyl group” for R means aC₃₋₁₀ cycloalkyl group (particularly preferably cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, octahydroindenyl,decahydronaphthyl, adamantyl, and bicyclo[2.2.1]heptyl) that may besubstituted with 1-4 substituents selected from the above-describedstraight chain or branched C₁₋₁₀ alkyl group, (particularly preferably aC₁₋₈ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, isopentyl, 2,2-dimethylpropyl,4-methylpentyl, 2-ethylbutyl, or the like), the above-described straightchain or branched C₂₋₁₀ alkenyl group (particularly preferably a C₂₋₈alkenyl group such as 1-methylvinyl, 2-methylvinyl, 3-methyl-3-propenyl,or the like), the above-described C₃₋₁₀ cycloalkyl group (particularlypreferably a C₃₋₇ cycloalkyl group such as cyclopropyl, cyclopentyl,cyclohexyl, or the like), the above-described C₅₋₈ cycloalkenyl group(particularly preferably a C₅₋₆ cycloalkenyl group such ascyclopentenyl, cyclohexenyl, or the like), the above-described C₃₋₁₀cycloalkyl C₁₋₁₀ alkyl group (particularly preferably a C₃₋₇ cycloalkylC₁₋₄ alkyl group such as cyclopropylmethyl, 2-cyclopropylethyl,2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, or the like),the above-described aryl group (particularly preferably a phenyl group),an oxo group, the above described aralkyl group (particularly preferablya phenyl C₁₋₄ lower alkyl group such as benzyl, phenethyl, or the like),and the above-described arylalkenyl group (particularly preferably a2-phenylvinyl group). Preferable examples thereof include2,2,3,3-tetramethylcyclopropyl, 1-isopentylcyclobutyl,1-isopropylcyclopentyl, 1-isobutylcyclopentyl, 1-isopentylcyclopentyl,1-cyclohexylmethylcyclopentyl, cyclohexyl, 1-methylcyclohexyl,1-ethylcyclohexyl, 1-propylcyclohexyl, 1-isopropylcyclohexyl,1-butylcyclohexyl, 1-isobutylcyclohexyl, 1-pentylcyclohexyl,1-isopentylcyclohexyl, 1-(2,2-dimethylpropyl)cyclohexyl,1-(4-methylpentyl)cyclohexyl, 1-(2-ethylbutyl) cyclohexyl,4-tert-butyl-1-isopentylcyclohexyl, 1-cyclopropylcyclohexyl,1-bicyclohexyl, 1-phenylcyclohexyl, 1-cyclopropylmethylcyclohexyl,1-cyclohexylmethylcyclohexyl, 1-(2-cyclopropylethyl) cyclohexyl,1-(2-cyclopentylethyl)cyclohexyl, 1-(2-cyclohexylethyl)cyclohexyl,4-methylcyclohexyl, 4-propylcyclohexyl, 4-isopropylcyclohexyl,4-tert-butylcyclohexyl, 4-pentylcyclohexyl, 4-bicyclohexyl,1-isopentylcycloheptyl, 3a-octahydroindenyl, 4a-decahydronaphthyl,1-adamantyl, and 7,7-dimethyl-1-(2-oxo)-bicyclo[2.2.1]heptyl. The siteof substitution is not specifically limited, but particularly preferablyat position 1. Any substitution group as described above may be used,but the straight chain or branched C₁₋₁₀ alkyl group is particularlypreferred.

The substituent for the “substituted or unsubstituted C₅₋₈ cycloalkenylgroup” for R is the same as that for the above “substituted orunsubstituted C₃₋₁₀ cycloalkyl group”. Specifically, it means acycloalkenyl group (especially cyclopentenyl and cyclohexenyl) that mayhave 1-4 substituents selected from the above-described straight chainor branched C₁₋₁₀ alkyl group (particularly preferably a C₁₋₈ alkylgroup such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,isopentyl, 2,2-dimethylpropyl, 4-methylpentyl, or the like), theabove-described straight chain or branched C₂₋₁₀ alkenyl group(particularly preferably a C₂₋₈ alkenyl group such as 1-methylvinyl,2-methylvinyl, 3-methyl-3-propenyl, and the like), the above-describedC₃₋₁₀ cycloalkyl group (particularly preferably a C₃₋₇ cycloalkyl groupsuch as cyclopropyl, cyclopentyl, cyclohexyl, or the like), theabove-described C₅₋₈ cycloalkenyl group (particularly preferably a C₅₋₆cycloalkenyl group like cyclopentenyl, cyclohexenyl, or the like), theabove-described C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group (particularlypreferably a C₃₋₇ cycloalkyl C₁₋₄ lower alkyl group such as cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl, cyclohexylmethyl,2-cyclohexylethyl, or the like), the above-described aryl group(particularly preferably a phenyl group), an oxo group, theabove-described aralkyl group (particularly preferably a phenyl C₁₋₄lower alkyl group such as benzyl, phenethyl, or the like), andarylalkenyl group (particularly preferably 2-phenylvinyl). Preferableexamples of the cycloalkenyl group includes 1-isopropyl-2-cyclopentenyl,1-isopropyl-3-cyclopentenyl, 1-isobutyl-2-cyclopentenyl,1-isobutyl-3-cyclopentenyl, 1-isopentyl-2-cyclopentenyl,1-isopentyl-3-cyclopentenyl, 1-cyclohexylmethyl-2-cyclopentenyl,1-cyclohexylmethyl-3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl,3-cyclohexenyl, 1-methyl-2-cyclohexenyl, 1-methyl-3-cyclohexenyl,1-ethyl-2-cyclohexenyl, 1-ethyl-3-cyclohexenyl, 1-propyl-2-cyclohexenyl,1-propyl-3-cyclohexenyl, 1-isopropyl-2-cyclohexenyl,1-isopropyl-3-cyclohexenyl, 1-butyl-2-cyclohexenyl,1-butyl-3-cyclohexenyl, 1-isobutyl-2-cyclohexenyl,1-isobutyl-3-cyclohexenyl, 1-pentyl-2-cyclohexenyl,1-pentyl-3-cyclohexenyl, 1-isopentyl-2-cyclohexenyl,1-isopentyl-3-cyclohexenyl, 1-(2,2-dimethylpropyl)-2-cyclohexenyl,1-(2,2-dimethylpropyl)-3-cyclohexenyl,1-(4-methylpentyl)-2-cyclohexenyl, 1-(4-methylpentyl)-3-cyclohexenyl,1-cyclopropyl-2-cyclohexenyl, 1-cyclopropyl-3-cyclohexenyl,1-cyclohexyl-2-cyclohexenyl, 1-cyclohexyl-3-cyclohexenyl,1-phenyl-2-cyclohexenyl, 1-phenyl-3-cyclohexenyl,1-cyclopropylmethyl-2-cyclohexenyl, 1-cyclo propylmethyl-3-cyclohexenyl,1-cyclohexylmethyl-2-cyclohexenyl, 1-cyclohexylmethyl-3-cyclohexenyl,1-(2-cyclopropylethyl)-2-cyclohexenyl,1-(2-cyclopropylethyl)-3-cyclohexenyl,1-(2-cyclopentylethyl)-2-cyclohexenyl,1-(2-cyclopentylethyl)-3-cyclohexenyl,1-(2-cyclohexylethyl)-2-cyclohexenyl, and1-(2-cyclohexylethyl)-3-cyclohexenyl. There is no special restriction onthe substitution position, but the particularly preferred position isposition 1. Any one of the above substituents may be used, but thestraight chain or branched C₁₋₁₀ alkyl group or the C₃₋₁₀ cycloalkylC₁₋₄ alkyl group is particularly preferred.

The “substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group”for R means a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group (particularlypreferably cyclohexylmethyl, 1-cyclohexylethyl,1-cyclohexyl-1-methylethyl, 1-cyclohexyl-2-methylpropyl,1-cyclohexyl-3-methylbutyl, 1-cyclohexylhexyl,1-cyclohexyl-4-methylpentyl, and 1-cyclohexylheptyl) C₁₋₁₀ alkyl groupof which is straight chain or branched and which may have 1-4substituents selected from the above-described C₃₋₁₀ cycloalkyl group(particularly preferably a C₃₋₇ cycloalkyl group such as cyclopentyl orcyclohexyl), the above-described C₅₋₈ cycloalkenyl group (particularlypreferably a C₅₋₇ cycloalkenyl group such as cyclopentenyl orcyclohexenyl), and the above-described aryl group (particularlypreferably a phenyl group). There is no special restriction on thesubstitution position. The above-described substituents may be placed atthe straight chain or branched C₁₋₁₀ alkyl moiety. Preferable examplesof the C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group include cyclohexylmethyl,1-cyclohexylethyl, cyclohexylcyclo-pentylmethyl, dicyclohexylmethyl,1-cyclohexyl-1-methylethyl, 1-cyclohexyl-2-methylpropyl,1-cyclohexyl-3-methylbutyl, 1-cyclohexyl-4-methylpentyl,1-cyclohexylhexyl, and 1-cyclohexylheptyl.

The “substituted or unsubstituted aryl group” for R means an aryl group(particularly preferably a phenyl group) that may have 1-4 substituentsselected from the above-described straight chain or branched C₁₋₆ alkylgroup (particularly preferably a tert-butyl group), the above-describedhalogen atom (particularly preferably fluorine and chlorine), and anitro group. Preferable examples of the aryl group are phenyl,2-chlorophenyl, 4-nitrophenyl, and 3,5-di-tert-butylphenyl.

The “substituted or unsubstituted aralkyl” for R means an aralkyl group(particularly preferably benzyl, benzhydryl, and trityl) which may havesubstituents selected from the above-described halogen atom(particularly preferably fluorine and chlorine), a nitro group, and ahydroxy group, and in which the C₁₋₄ lower alkyl group is straight chainor branched. There is no special restriction on the position ofsubstitution. The straight chain or branched C₁₋₄ lower alkyl moiety maybe substituted. Preferable examples of the aralkyl group are benzyl andtrityl.

The “substituted or unsubstituted 5- or 6-membered heterocyclic grouphaving 1-3 nitrogen, oxygen or sulfur atoms” for R means theabove-described heterocyclic group that may have 1-4 substituentsselected from the above-described straight chain or branched C₁₋₆ alkylgroup (particularly preferably a tert-butyl group), the above-describedhalogen atom (particularly preferably fluorine and chlorine), and anitro group. The heterocyclic group is preferably an aromaticheterocyclic group, particularly preferably furyl, thienyl, and pyridyl.

The “substituted or unsubstituted straight chain or branched C₁₋₁₀ alkylgroup” for R₁ means a straight chain or branched C₁₋₁₀ alkyl group thatmay have a substituent selected from the above-described halogen atom(particularly preferably fluorine and chlorine), the above-describedC₁₋₄ lower alkoxy group (particularly preferably a methoxy group), anamino group that may be substituted with the above-described C₁₋₄ loweralkyl group (particularly preferably a methyl group), theabove-described acyl group (particularly preferably an acetyl group), ora hydroxyl group, the above-described C₁₋₄ lower alkylthio group(particularly preferably a methylthio group), a carbamoyl group, ahydroxyl group, an acyloxy group having the above-described acyl group(particularly preferably an acetyloxy group), a carboxyl group, an acylgroup (particularly preferably a methoxycarbonyl group), and an aryloxygroup having the above-described substituted or unsubstituted aryl group(particularly preferably a phenoxy group and a 4-chlorophenoxy group).Preferable examples of the alkyl group include methyl, chloromethyl,ethyl, isopropyl, 1-methyl-2-pentyl, octyl, methoxymethyl,dimethylaminomethyl, acetylaminomethyl, 1-acetyl aminoethyl,1-acetylamino-2-methylpropyl, 1-acetylamino-3-methylbutyl,1-acetylamino-3-methylthiopropyl, 1-acetylamino-3-carbamoylpropyl,1-hydroxy-1-methylethyl, 1-acetyloxy-1-methylethyl, 4-carboxybutyl,2-methoxycarbonylethyl, phenoxymethyl, and 4-chlorophenoxymethyl.

The “C₁₋₄ lower alkoxy group” for R₁ is preferably a methoxy group and atert-butoxy group.

The “C₁₋₄ lower alkylthio group” for R₁ is preferably a methylthiogroup.

The “substituted or unsubstituted amino group” for R₁ means an aminogroup that may have a substituent selected from the above-described C₁₋₄lower alkyl group (particularly preferably ethyl, isopropyl, andtert-butyl), the above-described acyl group (particularly preferablyacetyl and benzoyl), and the above-described aryl group (particularlypreferably phenyl and 4-methoxyphenyl) that may be substituted with theabove-described C₁₋₄ lower alkoxy group. Preferable examples of theamino group are ethylamino, isopropylamino, tert-butylamino,phenylamino, and 4-methoxyphenylamino.

The “substituted or unsubstituted ureido group” for R₁ means a ureidogroup that may have a substituent selected from the above-described C₁₋₄lower alkyl group (particularly preferably methyl and ethyl), theabove-described acyl group (particularly preferably acetyl and benzoyl),and the above-described aryl group (particularly preferably phenyl and4-methoxyphenyl) that may be substituted with the above-described C₁₋₄lower alkoxy group, with an N,N′-diphenylureido group being preferred.

The “substituted or unsubstituted C₃₋₁₀ cycloalkyl group” for R₁ means aC₃₋₁₀ cycloalkyl group (particularly preferably cyclopropyl andcyclohexyl) that may have a substituent selected from theabove-described straight chain or branched C₁₋₁₀ alkyl group(particularly preferably methyl, tert-butyl, and isopentyl), an aminogroup, an amino group (particularly preferably methylamino, ethylamino,acetylamino, and benzylamino) that may be substituted with theabove-described C₁₋₄ lower alkyl or acyl groups. Preferable examples thecycloalkyl group are cyclopropyl, cyclohexyl, 1-methylcyclohexyl,1-isopentylcyclohexyl, 1-aminocyclohexyl, 1-acetylaminocyclohexyl, and4-tert-butylcyclohexyl.

The “substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group”for R₁ means a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group which may have asubstituent selected from the above-described C₃₋₁₀ cycloalkyl group(particularly preferably cyclopentyl and cyclohexyl), theabove-described C₅₋₈ cycloalkenyl group (particularly preferablycyclopentenyl and cyclohexenyl), and the above-described aryl group(particularly preferably a phenyl group) and in which the C₁₋₁₀ alkylmoiety is straight chain or branched. There is no special restriction onthe position of substitution. The straight chain or branched C₁₋₁₀ alkylmoiety may be substituted. A cyclohexylmethyl group is preferred as theC₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group.

The “substituted or unsubstituted aryl group” for R₁ means an aryl group(particularly preferably phenyl and naphthyl) that may have asubstituent selected from the above-described straight chain or branchedC₁₋₆ alkyl group (particularly preferably methyl and tert-butyl group),the above-described halogen atom (particularly preferably fluorine andchlorine), a nitro group, a hydroxyl group, the above-described C₁₋₄lower alkoxy group (particularly preferably a methoxy group), and theabove-described acyl group (particularly preferably a2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl group).Preferable examples of the aryl group include phenyl, 1-naphthyl,2-naphthyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl,2-methoxyphenyl, 2-nitrophenyl, 4-nitrophenyl,3,5-di-tert-butyl-4-hydroxyphenyl, and4-[2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl]phenyl.

The “substituted or unsubstituted aralkyl group” for R₁ means an aralkylgroup (particularly preferably benzyl, phenethyl, 3-phenylpropyl,naphthylmethyl, and biphenylmethyl) that may have a substituent selectedfrom the above-described halogen atom (particularly preferably fluorineand chlorine), a nitro group, an amino group (particularly preferablyamino, acetylamino, pivaloylamino, 1-methylcyclohexanecarbonyl-amino,tert-butoxycarbonylamino, and benzoylamino) that may be substituted withthe above-described C₁₋₄ lower alkyl group or the above-described acylgroup, and a hydroxyl group, and in which the C₁₋₄ lower alkyl group arestraight chain or branched. There is no special restriction on theposition of substitution. The straight chain or branched C₁₋₄ loweralkyl moiety may be substituted. Preferable examples of the aralkylgroup include benzyl, phenethyl, 3-phenylpropyl, 2-naphthylmethyl,4-biphenylmethyl, benzhydryl, 2-chlorophenylmethyl,3-chlorophenylmethyl, 4-chlorophenylmethyl, 2-nitrophenylmethyl,4-nitrophenylmethyl, 2-pivaloylaminophenylmethyl,2-(1-methylcyclohexanecarbonylamino)phenylmethyl,2-tert-butoxy-carbonylaminophenylmethyl, 3-acetylaminophenylmethyl,3-(1-methylcyclohexanecarbonylamino)phenylmethyl, α-aminobenzyl,α-acetylaminobenzyl, α-(1-methylcyclohexanecarbonylamino)benzyl,α-benzoylaminobenzyl, α-aminophenethyl, α-acetylaminophenethyl, and1-acetylamino-2-(4-hydorxyphenyl) ethyl.

The “substituted or unsubstituted arylalkenyl group” for R₁ means anarylalkenyl group (particularly phenylvinyl) that may have a substituentselected from the above-described straight chain or branched C₁₋₆ loweralkyl group (particularly preferably methyl and tert-butyl), theabove-described halogen atom (particularly preferably fluorine andchlorine), a nitro group, and a hydroxyl group, with a 2-phenylvinylgroup being preferred.

The “substituted or unsubstituted arylthio group” for R₁ means anarylthio group (particularly preferably a phenylthio group) that mayhave a substituent selected from the above-described halogen atom(particularly preferably fluorine and chlorine), a nitro group, and anamino group that may be substituted with the above-described C₁₋₄ loweralkyl group or the above-described acyl group (particularly preferablyamino, acetylamino, pivaloylamino, 1-methylcyclohexanecarbonylamino, andbenzoylamino), a hydroxyl group, and the above-described halo-C₁₋₄ loweralkyl group (particularly preferably a trifluoromethyl group).Preferably examples of the arylthio group include phenylthio,2-pivaloylaminophenylthio,2-(1-methylcyclohexanecarbonylamino)phenylthio, and 2-(1-methylcyclohexanecarbonylamino-4-trifluoromethyl)phenylthio.

The “substituted or unsubstituted 5- or 6-membered heterocyclic ringgroups with 1-3 nitrogen, oxygen, or sulfur atoms” for R₁ meansheterocyclic ring groups (particularly preferably an aromaticheterocyclic group such as pyridyl or a non-aromatic heterocyclic groupsuch as piperidyl or pyrrolidinyl) that may have substituents selectedfrom the above-described straight chain or branched C₁₋₆ alkyl group(particularly preferably a methyl group), a halogen atom (particularlypreferably fluorine and chlorine), the above-described acyl group(particularly preferably acetyl and benzoyl), and an oxo group.Preferable examples thereof are 3-pyridyl, 1-methyl-4-piperidyl,1-acetyl-4-piperidyl, 5-oxo-2-pyrrolidinyl, 1-acetyl-2-pyrrolidinyl, and1-benzoyl-2-pyrrolidinyl. A 4-piperidyl group such as1-methyl-4-piperidyl or 1-acetyl-4-piperidyl group is particularlypreferred.

The “substituted or unsubstituted 5- or 6-membered heteroarylalkylgroup” for R₁ means the above-described heteroarylalkyl group(particularly preferably a 2-tenyl group) that may be substituted withthe above-described straight chain or branched C₁₋₆ alkyl group(particularly preferably a methyl group) and the above-described halogenatom (particularly preferably fluorine and chlorine). A 2-tenyl group ispreferred.

The “substituted or unsubstituted C₁₋₄ lower alkyl group” for R₂ means aC₁₋₄ lower alkyl group (particularly preferably a methyl group) that mayhave 1-3 substituents selected from the above-described C₁₋₄ loweralkoxy group (particularly preferably a methoxy group), an amino groupthat may be substituted with the above-described C₁₋₄ lower alkyl oracyl group (particularly preferably a dimethylamino group), theabove-described C₁₋₄ lower alkylthio group (particularly preferably amethylthio group), a carbamoyl group, a hydroxyl group, a carboxylgroup, the above-described acyl group (particularly preferably amethoxycarbonyl group), and the above-described heterocyclic group(particularly preferably an aromatic heterocyclic group such as thienylor a non-aromatic heterocyclic group such as tetrahydrofuryl). Atetrahydrofurylmethyl group is preferred.

The “substituted or unsubstituted aryl group” for R₂ is the same as thatfor R₁. Preferable examples thereof are a phenyl group, a halogenatedphenyl group, an acylamino-substituted phenyl group, and the like.

The “halogen atom” for X₁, X₂, X₃, and X₄ means a halogen atom includingfluorine, chlorine, bromine, and the like, with fluorine and chlorinebeing preferred.

The “C₁₋₄ lower alkyl group” for X₁, X₂, X₃, and X₄ is preferably amethyl group.

The “halo-C₁₋₄ lower alkyl group” for X₁, X₂, X₃, and X₄ means a C₁₋₄lower alkyl group (particularly preferably a methyl group) substitutedwith the above-described halogen atom (particularly preferably fluorineand chlorine). A trifluoromethyl group is preferred.

The “C₁₋₄ lower alkoxy group” for X₁, X₂, X₃, and X₄ is preferably amethoxy group.

The “acyl group” for X₁, X₂, X₃, and X₄ is preferably a benzoyl group.

The “aryl group” for X₁, X₂, X₃, and X₄ is preferably a phenyl group.

The “1-substituted-C₃₋₁₀ cycloalkyl group” for R″ means a cycloalkylgroup (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cycloheptyl, preferably a C₅₋₇ cycloalkyl group, particularlypreferably a cyclohexyl group) that is substituted at position 1 withsubstituents selected from the above-described straight chain orbranched C₁₋₁₀ alkyl group (particularly preferably a C₁₋₈ alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,isopentyl, 2,2-dimethylpropyl, 4-methylpentyl, or 2-ethylbutyl), theabove-described straight chain or branched C₂₋₁₀ alkenyl group(particularly preferably a C₂₋₈ alkenyl group such as 1-methylvinyl,2-methylvinyl, or 3-methyl-3-propenyl), the above-described C₃₋₁₀cycloalkyl (particularly preferably a C₃₋₇ cycloalkyl group such ascyclopropyl, cyclopentyl, or cyclohexyl), the above-described C₅₋₈cycloalkenyl group (particularly preferably a C₅₋₆ cycloalkenyl groupsuch as cyclopentenyl or cyclohexenyl), the above-described C₃₋₁₀cycloalkyl C₁₋₁₀ alkyl group (particularly preferably a C₃₋₇ cycloalkylC₁₋₄ lower alkyl group such as cyclopropylmethyl, 2-cyclopropylethyl,2-cyclopentylethyl, cyclohexylmethyl, or 2-cyclohexylethyl), theabove-described aryl group (particularly preferably a phenyl group), theabove-described aralkyl group (particularly preferably a phenyl C₁₋₄lower alkyl group such benzyl and phenethyl), and an arylalkenyl group(particularly preferably 2-phenylvinyl). Preferable examples of the1-substituted-C₃₋₁₀ cycloalkyl group include 1-isopentylcyclobutyl,1-isopropylcyclopentyl, 1-isobutylcyclopentyl, 1-isopentyl cyclopentyl,1-cyclohexylmethylcyclopentyl, 1-methylcyclohexyl, 1-ethylcyclohexyl,1-propylcyclohexyl, 1-isopropylcyclohexyl, 1-butylcyclohexyl,1-isobutylcyclohexyl, 1-pentylcyclohexyl, 1-isopentylcyclohexyl,1-(2,2-dimethylpropyl)cyclohexyl, 1-(4-methylpentyl)cyclohexyl,1-(2-ethylbutyl)cyclohexyl, 1-cyclopropylcyclohexyl, 1-bicyclohexyl,1-phenylcyclohexyl, 1-cyclopropylmethylcyclohexyl,1-cyclohexylmethylcyclohexyl, 1-(2-cyclopropylethyl)cyclohexyl,1-(2-cyclopentylethyl)cyclohexyl, 1-(2-cyclohexylethyl)cyclohexyl, and1-isopentylcycloheptyl. The straight chain or branched C₁₋₁₀ alkyl groupis particularly preferable as a substituent at position 1.

The “1-substituted-C₅₋₈ cycloalkenyl group” for R″ means a cycloalkenylgroups (particularly preferably a C₅₋₆ cycloalkenyl group such ascyclopentenyl or cyclohexenyl) that is substituted at position 1 withsubstituents selected from the above-described straight chain orbranched C₁₋₁₀ alkyl group (particularly preferably a C₁₋₈ alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,isopentyl, 2,2-dimethyl propyl, and 4-methylpentyl), the above-describedstraight chain or branched C₂₋₁₀ alkenyl group (particularly preferablya C₂₋₈ alkenyl group such as 1-methylvinyl, 2-methylvinyl, or3-methyl-3-propenyl), the above-described C₃₋₁₀ cycloalkyl group(particularly preferably a C₃₋₇ cycloalkyl group such as cyclopropyl,cyclopentyl, or cyclohexyl), the above-described C₅₋₈ cycloalkenyl group(particularly preferably a C₅₋₆ cycloalkenyl group such as cyclopentenylor cyclohexenyl), the above-described C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group(particularly preferably a C₃₋₇ cycloalkyl C₁₋₄ lower alkyl group suchas cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl,cyclohexylmethyl, or 2-cyclohexylethyl), the above-described aryl group(particularly preferably a phenyl group), the above-described aralkylgroup (particularly preferably a phenyl C₁₋₄ lower alkyl group such asbenzyl or phenethyl), and the above-described arylalkenyl group(particularly preferably a 2-phenylvinyl group). Preferable examples ofthe 1-substituted-C₅₋₈ cycloalkenyl group include1-isopropyl-2-cyclopentenyl, 1-isopropyl-3-cyclopentenyl,1-isobutyl-2-cyclopentenyl, 1-isobutyl-3-cyclopentenyl,1-isopentyl-2-cyclopentenyl, 1-isopentyl-3-cyclopentenyl,1-cyclohexylmethyl-2-cyclopentenyl, 1-cyclohexylmethyl-3-cyclopentenyl,1-methyl-2-cyclohexenyl, 1-methyl-3-cyclohexenyl,1-ethyl-2-cyclohexenyl, 1-ethyl-3-cyclohexenyl, 1-propyl-2-cyclohexenyl,1-propyl-3-cyclohexenyl, 1-isopropyl-2-cyclohexenyl,1-isopropyl-3-cyclohexenyl, 1-butyl-2-cyclohexenyl,1-butyl-3-cyclohexenyl, 1-isobutyl-2-cyclohexenyl,1-isobutyl-3-cyclohexenyl, 1-pentyl-2-cyclohexenyl,1-pentyl-3-cyclohexenyl, 1-isopentyl-2-cyclohexenyl,1-isopentyl-3-cyclohexenyl, 1-(2,2-dimethylpropyl)-2-cyclohexenyl,1-(2,2-dimethylpropyl)-3-cyclohexenyl,1-(4-methylpentyl)-2-cyclohexenyl, 1-(4-methylpentyl)-3-cyclohexenyl,1-cyclopropyl-2-cyclohexenyl, 1-cyclopropyl-3-cyclohexenyl,1-cyclohexyl-2-cyclohexenyl, 1-cyclohexyl-3-cyclohexenyl,1-phenyl-2-cyclohexenyl, 1-phenyl-3-cyclohexenyl,1-cyclopropylmethyl-2-cyclohexenyl, 1-cyclopropylmethyl-3-cyclohexenyl,1-cyclohexylmethyl-2-cyclohexenyl, 1-cyclohexylmethyl-3-cyclohexenyl,1-(2-cyclopropylethyl)-2-cyclohexenyl,1-(2-cyclopropylethyl)-3-cyclohexenyl,1-(2-cyclopentylethyl)-2-cyclohexenyl,1-(2-cyclopentylethyl)-3-cyclohexenyl,1-(2-cyclohexylethyl)-2-cyclohexenyl, and1-(2-cyclohexylethyl)-3-cyclohexenyl. The straight chain or branchedC₁₋₁₀ alkyl group is particularly preferable as a substituent atposition 1.

The “prodrug compound” means the derivatives of compounds of the presentinvention having a chemically or metabolically degradable group, whichexhibit pharmaceutical activity by degradation through hydrolysis orsolvolysis, or under physiological conditions.

The “pharmaceutically acceptable salt” means any compound that is anatoxic salt formed with the compound represented by the above formula(I). Examples of such a salt include inorganic acid salts such ashydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates,phosphates, carbonates, bicarbonates, or perchlorates; organic acidsalts such as formates, acetates, trifluoroacetates, propionates,tartrates, glycolates, succinates, lactates, maleates, hydroxymaleates,methylmaleates, fumarates, adipiates, tartrates, malates, citrates,benzoates, cinnamates, ascorbates, salicylates, 2-acetoxybenzoates,nicotinates, or isonicotinates; sulfonates such as methane sulfonates,ethane sulfonates, isethionates, benzene sulfonates, p-toluenesulfonates, or naphthalene sulfonates; salts of acidic amino acids suchas aspargates or glutamates; alkali metal salts such as sodium salts orpotassium salts, alkaline earth metal salts such as magnesium salts orcalcium salts; ammonium salts; organic base salts such astrimethylamines, triethylamines, pyridine salts, picoline salts,dicyclohexylamine salts or N,N′-dibenzyl ethylenediamine salts; andsalts of amino acids such as lysine salts or arginine salts. Dependingon the circumstances, hydrates or solvates with alcohols may be used.

More specifically, a 1-isobutylcyclohexyl group, a 1-(2-ethylbutyl)cyclohexyl group, and a 1-isopentylcyclohexyl group are particularlypreferable as R in the formula (I), —CO— is particularly preferable asY, a hydrogen atom is particularly preferable as X₁, X₂, X₃, and X₄, andan isobutyryl group and a 1-acetyl-4-piperidine carbonyl group areparticularly preferable as Z.

The compound of the present invention inhibits CETP activity and isexpected as a conventionally unknown, new type of a preventive ortherapeutic agent for hyperlipidemia or atherosclerotic diseases.

When used as a pharmaceutical preparation, the compound of the presentinvention represented by the formula (I) or a pharmaceuticallyacceptable salt thereof can be usually used together with knownpharmacologically acceptable carriers, excipients, diluents, extenders,disintegrators, stabilizers, preservatives, buffers, emulsifiers,aromatics, colorants, sweeteners, viscosity increasing agents, flavorimproving agents, solubilizers, and other additives. More specifically,the compound can be formulated into dosage forms, such as tablets,pills, powders, granules, suppositories, injections, eye drops, liquiddrugs, capsules, troches, aerosols, elixirs, suspensions, emulsions, orsyrup, together with water, plant oil, alcohols such as ethanol orbenzyl alcohol, polyethylene glycol, glyceroltriacetate gelatin,lactose, carbohydrates such as starch, magnesium stearates, talc,lanolin, and vaseline, which can be administered orally or parenterally.

The above pharmaceutical preparations contain the compound of thepresent invention represented by the formula (I) or a pharmaceuticallyacceptable salt thereof in an amount effective to inhibit CETP activityand prevent or treat hyperlipidemia, atherosclerotic diseases, or thelike diseases attributable to CETP activity. One skilled in the art caneasily determine such an effective amount.

Doses may vary depending on the type and degree of diseases, thecompounds to be administered, the route of administration, the age, sex,and body weight of the patients. In the case of oral administration, itis usually desirable to administer the compound (I) to an adult 1-1000mg, particularly 50-800 mg per day.

The compound of the present invention can be produced using thefollowing method, but it is needless to say that the method of producingthe compound of the present invention is not limited to this method.

[Step 1]

The compound (II-2) (in the formula R, X₁, X₂, X₃, X₄, and Y are asdescribed above) can be synthesized by reacting the compound (VI) (inthe formula X₁, X₂, X₃, and X₄ are as described above) with the compound(XII) (in the formula X represents a halogen atom and R and Y are asdescribed above) in the presence of a base such as pyridine,triethylamine, N-methylmorpholine, or N-methylpiperazine in an organicsolvent such as methylene chloride, chloroform, toluene, ether,tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, or hexane,water, or a mixture of these solvents, or in the absence of a solvent,under cooling through heating temperature.

The compound (III-2) can be synthesized from the compound (II-2) by thefollowing step 2.

[Step 2]

The compound (III-2) (in the formula R, X₁, X₂, X₃, X₄, and Y are asdescribed above) can be synthesized by allowing the compound (II-2) (inthe formula R, X₁, X₂, X₃, X₄, and Y are as described above) to react inthe presence of a reducing agent such as sodium borohydride, lithiumborohydride, aluminum lithium hydride, triphenylphosphine, zinc, or tin,in an organic solvent such as methanol, ethanol, ether, dioxane,tetrahydrofuran, diisopropyl ether, dimethoxyethane, toluene, hexane,acetone, or acetic acid, water, or a mixture of these solvents, undercooling through heating temperature.

The compound (II-2) or (IV-2) can also be synthesized from the compound(III-2) using the following step 3 or 4.

[Step 3]

The compound (II-2) (in the formula R, X₁, X₂, X₃, X₄, and Y are asdescribed above) can be synthesized by allowing the compound (III-2) (inthe formula R, X₁, X₂, X₃, X₄, and Y are as described above) to react inthe presence of an oxidizing agent such as iodine, hydrogen peroxide,potassium permanganate, or dimethylsulfoxide, in an organic solvent suchas methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropylether, dimethoxyethane, acetone, toluene, hexane, dimethylformamide, oracetic acid, water, or a mixture of these solvents, or in the absence ofa solvent, under cooling through heating temperature.

[Step 4]

The compound (IV-2) (in the formula R, R₁, X₁, X₂, X₃, X₄, Y, and Y₁ areas described above) can be synthesized by reacting the compound (III-2)(in the formula R, X₁, X₂, X₃, X₄, and Y are as described above) withacid halide R₁—YX (in the formula R₁, X, and Y are as described above),isocyanate R₁—NY (in the formula R₁ and Y are as described above),carbonic halide R₁—O—YX (in the formula R₁, X, and Y are as describedabove), or thiocarbonic halides R₁—S—YX (in the formula R₁, X and Y areas described above) in the presence of a base such as pyridine,triethylamine, N-methylmorpholine, or N-methylbipiperazine, in anorganic solvent such as methylene chloride, chloroform, toluene, ether,dioxane, tetrahydro furan, diisopropyl ether, dimethoxy ethane, orhexane, water, or a mixture of these solvents, or in the absence of asolvent, under cooling through heating temperature. Alternatively, thecompound (IV-2) can be synthesized by reacting the compound (III-2) withcarboxylic acid R₁—COOH (in the formula R₁ is as described above) orthiocarboxylic acid R₁—YSH (in the formula R₁ and Y are as describedabove) using a coupling agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,dicyclohexylcarbodiimide, diphenylphosphorylazide, orcarbonyldiimidazole, in the presence of an activating agent, ifrequired, such as 1-hydroxybenzotriazole, hydroxysuccinimide, orN-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, in an organicsolvent such as dimethylformamide, dichloromethane, chloroform,acetonitrile, tetrahydrofuran, dimethylsufoxide, carbon tetrachloride,or toluene, or a mixture of these solvents, under cooling throughheating temperature. (The reaction may be carried out in the presence ofa base such as pyridine or triethylamine.) Furthermore, the compound(IV-2) can be synthesized by reacting the compound (III-2) withcarboxylic acid R₁—COOH (in the formula R₁ is as described above) in thepresence of a base such as triethylamine or pyridine and in the presenceof ethyl chlorocarbonate or the like, in a organic solvent such as ethylacetate or tetrahydrofuran, or a mixture of these solvents, undercooling through heating temperature. When R₁ has a carboxyl group, thisabove step may be conducted using the corresponding ester to obtain thecompound by hydrolysis with acid using the known method.

The compound (IV-2) can also be synthesized by subsequently conductingthe step 4 following the above step 2 or the step 7 below, or the step10 below, without isolating the compound (III-2).

The compound (V-2) can be synthesized by conducting the following step 5or 5′. The step 5 is suitable especially when R₂ is the lower alkylgroup that may have substituents and the step 5′ is suitable especiallywhen R₂ is the aryl group that may have substituents.

[Step 5]

The compound (V-2) (in the formula R, R₂, X₁, X₂, X₃, X₄, and Y are asdescribed above) can be synthesized by allowing R₂—X (in the formula R₂and X is as described above) and a sulfur compound like sodiumthiosulfate to react in an organic solvent such as ethanol, methanol,tetrahydrofuran, dioxane, dimethoxyethane, acetone, or acetonitrile,water, or a mixture of these solvents, at room temperature throughheating temperature, and adding the compound (III-2) (in the formula R,X₁, X₂, X₃, X₄, and Y are as described above) and a basic aqueoussolution such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, or sodium bicarbonate to the resultingsolution under ice-cooling through heating temperature.

[Step 5′]

The compound (V-2) (in the formula R, R₂, X₁, X₂, X₃, X₄, and Y are asdescribed above) can be synthesized by reacting R₂—SH (in the formula R₂is as described above) with trimethylsilane-imidazole in carbontetrachloride under ice-cooling through room temperature, adding to theresulting solution a reaction mixture resulted from reacting thecompound (II-2) (in the formula R, X₁, X₂, X₃, X₄, and Y are asdescribed above) with sulfuryl chloride in carbon tetrachloride in thepresence of a base such as triethylamine, pyridine, N-methylmorpholine,or N-methylpiperazine under ice-cooling through room temperature, andallowing the resulting mixture to react.

The compound (III-2) can also be synthesized using the following scheme.

[Step 6]

The compound (XI) (in the formula R, X₁, X₂, X₃, X₄, and Y are asdescribed above) can be synthesized by reacting the compound (X) (in theformula X₁, X₂, X₃, and X₄ are as described above) with the compound(XII) (in the formula R, X, and Y are as described above) in thepresence of a base such as pyridine, triethylamine, N-methylmorpholine,or N-methylpiperazine, in an organic solvent such as methylene chloride,chloroform, toluene, ether, dioxane, tetrahydrofuran, diisopropyl ether,dimethoxyethane, or hexane, water, or a mixture of these solvents, or inthe absence of a solvent, under cooling through heating temperature.

[Step 7]

The compound (III-2) (in the formula R, X₁, X₂, X₃, X₄, and Y are asdescribed above) can be synthesized by allowing the compound (XI) (inthe formula R, X₁, X₂, X₃, X₄, and Y are as described above) to react inthe presence of a base such as sodium acetate, sodium hydroxide,potassium hydroxide, potassium carbonate, sodium carbonate, or sodiumbicarbonate, in an organic solvent such as methanol, ethanol,tetrahydrofuran, dioxane, dimethoxyethane, ether, or diisopropyl ether,water, or a mixture of these solvents, under ice-cooling through heatingtemperature.

The compound (III-2) can also be synthesized by the following scheme.

[Step 8]

The compound (VIII) (in the formula R₁₁ and R₁₂ may be the same ordifferent and are a lower alkyl group such as methyl or ethyl, and X₁,X₂, X₃, and X₄ are as described above) can be synthesized by reactingthe compound (VII) (in the formula X₁, X₂, X₃, and X₄ are as describedabove) with the compound (XIII) (in the formula R₁₁, R₁₂, and X are asdescribed above) in the presence of a base such as sodium hydride,triethylamine, or N-methylmorpholine, in an organic solvent such asdimethylformamide, tetrahydrofuran, dioxane, or dimethoxyethane or amixture of these solvents, under cooling through heating temperature,and allowing the resulting product to react in an organic solvent suchas phenylether or sulfolane or a mixture of these solvents, or in theabsence of a solvent, under heating.

[Step 9]

The compound (IX) (in the formula R, R₁₁, R₁₂, X₁, X₂, X₃, X₄, and Y areas described above) can be synthesized by allowing the compound (VIII)(in the formula R₁₁, R₁₂, X₁, X₂, X₃, and X₄ are as described above) toreact in the presence of a reducing agent such as stannous chloride,zinc, iron, sodium dithionite, sodium sulfide, or sodium disulfide, inan organic solvent such as ethyl acetate, acetic acid, methanol,ethanol, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane,or toluene, water, or a mixture of these solvents, under cooling throughheating temperature, and reacting the resulting product with thecompound (XII) (in the formula R, X, and Y are as described above) inthe presence of a base such as pyridine, triethylamine,N-methylmorpholine, or N-methylpiperazine, in an organic solvent such aschloroform, methylene chloride, tetrahydrofuran, ether, dioxane,diisopropyl ether, dimethoxyethane, toluene, or hexane, water or amixture of these solvents, or in the absence of a solvent, under coolingthrough heating temperature.

[Step 10]

The compound (III-2) (in the formula R, X₁, X₂, X₃, X₄, and Y are asdescribed above) can be synthesized by allowing the compound (IX) (inthe formula R, R₁₁, R₁₂, X₁, X₂, X₃, X₄, and Y are as described above)to react in the presence of a base such as potassium hydroxide, sodiumhydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate,in an organic solvent such as methanol, ethanol, tetrahydrofuran,dioxane, dimethoxyethane, ether, or diisopropyl ether, water, or amixture of these solvents, under cooling through heating temperature.

The compound (VI) can also be synthesized from the compound (VIII) bythe following step 11.

[Step 11]

The compound (VI) (in the formula X₁, X₂, X₃, and X₄ are as describedabove) can be synthesized by allowing the compound (VIII) (in theformula R₁₁, R₁₂, X₁, X₂, X₃, and X₄ are as described above) to react inthe presence of a reducing agent such as stannous chloride, zinc, iron,sodium dithionite, sodium sulfide, and sodium disulfide, in an organicsolvent such as ethyl acetate, acetic acid, methanol, ethanol, ether,tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, andtoluene, water or a mixture of these solvents, under cooling throughheating temperature, allowing the resulting product to react in thepresence of a base such as potassium hydroxide, sodium hydroxide,potassium carbonate, sodium carbonate, or sodium bicarbonate, in anorganic solvents such as methanol, tetrahydrofuran, ethanol, dioxane,ether, diisopropyl ether, or dimethoxyethane, water, or a mixture ofthese solvents, under cooling through heating temperature, and allowingthe product to react in the presence of an oxidizing agent such asiodine, hydrogen peroxide, potassium permanganate, or dimethylsufoxide,in an organic solvent such as methanol, ethanol, ether, dioxane,tetrahydrofuran, diisopropyl ether, dimethoxyethane, acetone, toluene,hexane, dimethylformamide, or acetic acid, water, or a mixture of thesesolvents, or in the absence of a solvent, under cooling through heatingtemperature.

The compound (I) thus obtained can be isolated and purified using theknown method for separation and purification, such as concentration,concentration under reduced pressure, extraction, crystallization,recrystallization, or chromatography.

The compound of the present invention contains one or more ofstereoisomers due to the presence of the asymmetric carbon. Such isomersand mixtures thereof are all included in the scope of the presentinvention.

BEST MODE FOR CARRYING OUT THE INVENTION

In the following the present invention will be described in detail withreference to Examples and Test Example, but the present invention is notlimited thereto.

EXAMPLE 1 Synthesis of bis-[2-(pivaloylamino)phenyl]disulfide (formula(I); R=t-butyl, X₁, X₂, X₃, X₄=a hydrogen atom, Y=carbonyl,Z=2-(pivaloylamino)phenylthio)

Step 1) A mixture of bis-(2-aminophenyl) disulfide (8.00 g), pyridine(6.5 ml), and chloroform (150 ml) was stirred at 0° C., to whichpivaloyl chloride (83 ml) was added dropwise. After completion ofaddition, the organic layer was washed with water and saturated brine.After drying the organic layer over anhydrous sodium sulfate andevapolation, solid material was obtained. The solid thus obtained waswashed with ether-hexane and collected by filtration to give the desiredcompound (11.15 g, yield: 83%).

EXAMPLE 2 Synthesis ofbis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl disulfide(formula (I); R=1-(2-ethylbutyl)cyclohexyl, X₁, X₂, X₃, X₄=a hydrogenatom, Y=carbonyl,Z=2-[1-(2-ethylbutyl)-cyclohexanecarbonylamino]phenylthio)

i) A suspension of 60% sodium hydride (980 mg) in tetrahydrofuran (80ml) was stirred at room temperature and a tetrahydrofuran solution (10ml) containing cyclohexanecarboxylic acid (3.00 g) was added dropwisethereto. After completion of addition, a mixture was stirred for 1 hourand cooled to 0° C., followed by adding a cyclohexane solution (18.7 ml)containing 1.5 M lithium isopropylamide dropwise thereto. Then, afterstirring at room temperature for 1.5 hours and cooling to 0° C., atetrahydrofuran solution (10 ml) containing 1-bromo-2-ethylbutane (4.64g) was added dropwise thereto. The solution was gradually warmed to roomtemperature and stirred overnight. Water and a 10% hydrochloridesolution were added to this reaction solution and the solution wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. After drying,the resulting solution was concentrated to obtain1-(2-ethylbutyl)cyclohexanecarboxylic acid (3.17 g, yield: 64%).

ii) A mixture of 1-(2-ethylbutyl)cyclohexane carboxylic acid (1.50 g)obtained in the above i), oxalylchloride (0.85 ml), methylene chloride(20 ml), and a small amount of dimethylformamide was stirred at roomtemperature for 1 hour, concentrated under reduced pressure to obtain1-(2-ethylbutyl)cyclohexanecarbonyl chloride as a crude product.

Step 1) A pyridine solution (20 ml) containing bis-(2-aminophenyl)disulfide (825 mg) was stirred at room temperature and a crude productof 1-(2-ethylbutyl)cyclohexanecarbonylchloride obtained in the above ii)was added dropwise thereto. After completion of addition, the solutionwas stirred overnight at 100° C. After concentration under reducedpressure, water was added to the reaction solution and the solution wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate, followed byconcentration. The resulting residue was purified by silica gel columnchromatography (a developing solvent; hexane:ethyl acetate=15:1) toobtain the desired compound (667 mg, yield: 32%).

EXAMPLES 3-8

The compounds shown in Tables 1 and 2 were obtained in the same manneras in Examples 1 and 2.

TABLE 1 Example Compound m.p. (° C.) ¹H NMR(CDCl₃300MHz) 1

86-87 8.52(2H, brs) 8.46(2H, dd, J=1.5, 8.4Hz) 7.40(2H, ddd, J=1.5, 7.8,8.4Hz) 7.21(2H, dd, J=1.5, 7.8Hz) 6.94(2H, dt, J=1.5, 7.8Hz) 1.25(18H,s) 2

Amorphous 8.58(2H, brs) 8.48(2H, dd, J=1.5, 8.4Hz) 7.42(2H, ddd, J=1.5,7.8, 8.4Hz) 7.13(2H, dd, J=1.5, 7.8Hz) 6.92(2H, dt, J=1.5, 7.8Hz)1.90-2.10(4H, m) 1.10-1.80(30H, m) 0.78(12H, t, J=7.2Hz) 3

144-145 8.93(2H, brs) 8.50(2H, dd, J=1.5, 8.4Hz) 7.69(4H, dd, J=1.5,8.4Hz) 7.40-7.60(8H, m) 7.31(2H, dt, J=1.5, 8.4Hz) 6.95(2H, dt, J=1.5,7.8Hz) 4

156-157 8.78(2H, brs) 8.40(2H, dd, J=1.5, 8.4Hz) 7.55(2H, dd, J=1.2,5.1Hz) 7.20-7.45(6H, m) 7.10(2H, dt, J=1.2, 5.1Hz) 6.95(2H, dt, J=1.5,7.8Hz) 5

157-158 8.44(2H, dd, J=1.5, 8.4Hz) 8.04(2H, brs) 7.41(2H, ddd, J=1.5,7.8, 8.4Hz) 7.24(2H, dd, J=1.5, 7.8Hz) 6.96(2H, dt, J=1.5, 7.8Hz)2.05-2.20(2H, m) 1.20-1.70(16H, m) 0.93(12H, t, J=7.2Hz) 6

Amorphous 8.51(2H, brs) 8.48(2H, dd, J=1.5, 8.4Hz) 7.40(2H, ddd, J=1.5,7.8, 8.4Hz) 7.22(2H, dd, J=1.5, 7.8Hz) 6.95(2H, dt, J=1.5, 7.8Hz)1.80-2.00(4H, m) 1.25-1.70(16H, m) 1.18(6H, s)

TABLE 2 Example Compound m.p (° C.) ¹H NMR(CDCl₃300MHz) 7

Amorphous 8.46(2H, dd, J=1.5, 8.4Hz) 8.41(2H, brs) 7.40(2H, ddd, J=1.5,7.8, 8.4Hz) 7.13(2H, dd, J=1.5, 7.8Hz) 6.91(2H, dt, J=1.5, 7.8Hz)2.00-2.15(4H, m) # 1.45-1.75(18H, m) 1.15-1.25(4H, m) 0.87(12H, d,J=6.6Hz) 8

Amorphous 8.50(2H, brs) 8.49(2H, dd, J=1.5, 8.4Hz) 7.41(2H, ddd, J=1.5,7.8, 8.4Hz) 7.15(2H, dd, J=1.5, 7.8Hz) 6.92(2H, dt, J=1.5, 7.8Hz)1.89-2.00(4H, m) 1.10-1.66(26H, m) 0.85(12H, d, J=6.6Hz)

The compounds 1-1 through 1-19 shown in Tables 3 and 4 were obtained inthe same manner as in Examples 1 and 2.

TABLE 3 No. Compound 1-1 

1-2 

1-3 

1-4 

1-5 

1-6 

1-7 

1-8 

1-9 

1-10

1-11

1-12

1-13

1-14

1-15

1-16

1-17

1-18

1-19

TABLE 4 No. Compound 1-13

1-14

1-15

1-16

1-17

1-18

1-19

EXAMPLE 9 Synthesis of N-(2-mercaptophenyl)-2,2-dimethylpropioneamide(formula (I); R=t-butyl, X₁, X₂, X₃, X₄=a hydrogen atom, Y=carbonyl, Z=ahydrogen atom)

Step 2) A mixture of bis-[2-(pivaloylamino)phenyl]disulfide (300 mg)obtained in Example 1 above in methanol (0.4 ml)-tetrahydrofuran (4 ml)was stirred at room temperature. Sodium borohydride (70 mg) was addedthereto and the resulting solution was refluxed under heating for 4hours. After cooling and addition of 10% hydrochloric acid, theresulting solution was extracted with ethyl acetate. The organic layerwas washed with water, and saturated brine, and was dried over anhydroussodium sulfate. After drying, the solution was concentrated and theresulting residue was separated and purified by silica gel columnchromatography (a developing solvent; hexane:ethyl acetate=10:1) toobtain the desired compound (84 mg, yield: 28%).

EXAMPLE 10 Synthesis ofN-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide (formula(I); R=1-(2-ethylbutyl)cyclohexyl, X₁, X₂, X₃, X₄=a hydrogen atom,Y=carbonyl, Z=a hydrogen atom)

Step 2) A mixture ofbis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide (667mg) obtained in Example 2 above, triphenylphosphine (577 mg), dioxane (8ml), and water (4 ml) was stirred for 1 hour at 50° C. After allowingthe mixture to cool, a 1 N aqueous sodium hydroxide was added thereto.The aqueous layer was washed with hexane and neutralized with a 10%hydrochloride solution. After extraction with ethyl acetate, thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. After drying, the solution was concentrated and thethus-obtained residue was purified by silica gel column chromatography(a developing solvent; hexane:ethyl acetate=15:1), which resulted in thedesired compound (378 mg, yield: 56%).

TABLE 5 Example Compound m.p. (° C.) ¹H NMR(CDCl₃300MHz)  9

69-71 8.42(1H, brs) 8.31(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.30(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.08(1H, s) 1.36(9H, s) 10

68.5-74.0 8.45(1H, brs) 8.33(1H, dd, J=1.5, 8.4Hz) 7.51(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.05-2.25(2H, m) 1.20-1.80(15H, m) 0.79(6H, t, J=6.9Hz)

EXAMPLE 11 Synthesis ofN-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide (formula (I);R=1-isopentylcyclohexyl, X₁, X₂, X₃, X₄=a hydrogen atom, Y=carbonyl, Z=ahydrogen atom)

Step 6)N-[2-(1-isopentylcyclohexane)carbonylthiophenyl]-1-isopentylcyclohexanecarboxamide(formula (XI); R=1-isopentylcyclohexyl, X₁, X₂, X₃, X₄=a hydrogen atom,Y=carbonyl)

A pyridine solution (500 ml) containing 2-aminothiophenol (15.8 g) wasstirred at room temperature and 2 equal volumes of1-isopentylcyclohexanecarbonyl chloride was added dropwise thereto.After completion of addition, the solution was stirred for 2 hours at60° C. and allowed to cool. After removal of pyridine under reducedpressure, water was added and the solution was extracted with ethylacetate. The organic layer was washed with an aqueous solution ofsaturated sodium bicarbonate, hydrochloric acid, and saturated brine, inthis order, and dried over anhydrous sodium sulfate. The resultingsolution was concentrated under reduced pressure to give the desiredcompound in the form of a crude oily substance (60 g).

Step 7) The crude product obtained in the above step 6) (60 g) wasdissolved in a mixed solvent of methanol (60 ml)-tetrahydrofuran (60 ml)in the atmosphere of argon. Potassium hydroxide (24.2 g) was addedthereto and the solution was stirred for 1 hour at room temperature.After stirring, water (50 ml) was added, the solution was washed withhexane (50 ml×3), and the aqueous layer was acidified with potassiumhydrogen sulfate, followed by extraction with chloroform. The organiclayer was washed with water and saturated brine, dried over anhydroussodium sulfate, and the solvent was removed by evapolation under reducedpressure. The resulting deposited crystalline product was washed withpentane and collected by filtration to obtain the desired compound (23.1g, yield: 60%).

EXAMPLE 12-18

The compounds shown in Tables 6 and 7 were obtained in the same manneras in Example 11.

TABLE 6 Example Compound m.p. (° C.) ¹H NMR (CDCl₃300MHz) 11

109-110 8.34(1H, brs) 8.30(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.01(1H, s) 1.10-2.20(15H, m) 0.85(6H, d, J=6.6Hz) 12

82-83 8.42(1H, brs) 8.31(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.04-2.20(2H, m) 1.25-1.75(8H, m) 1.30(3H, s) 13

66-68 8.27(1H, dd, J=1.5, 8.4Hz) 8.26(1H, brs) 7.50(1H, dd, J=1.5,7.8Hz) 7.30(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.06(1H, s) 2.15-2.30(2H, m) 1.40-1.80(9H, m) 1.15(2H, m) 0.85(6H, d,J=6.6Hz) 14

120-121 8.37(1H, brs) 8.35(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.12-2.20(2H, m) 1.15-1.83(9H, m) 0.97(6H, d, J=6.9Hz) 15

84-85 8.38(1H, brs) 8.32(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.05-2.19(2H, m) 1.20-1.70(10H, m) 0.90(3H, t, J=7.2Hz) 16

93-94 8.38(1H, brs) 8.32(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.30(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.05-2.20(2H, m) 1.20-1.70(12H, m) 0.88(3H, t, J=7.2Hz)

TABLE 7 Example Compound m.p. (° C.) ¹H NMR(CDCl₃300MHz) 17

97-98 8.37(1H, brs) 8.31(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.301H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.05-2.20(2H, m) 1.20-1.70(14H, m) 0.87(3H, t, J=7.2Hz) 18

92-93 8.42(1H, brs) 8.32(1H, dd, J=1.5, 8.4Hz) 7.51(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.06-2.20(2H, m) 1.20-1.95(11H, m) 0.89(6H, d, J=6.6Hz)

Further, the compounds 11-1 and 11-2 shown in Table 8 were obtained inthe same manner as in Example 11.

TABLE 8 No. Compound 11-1

11-2

EXAMPLE 19 Synthesis ofN-(2-mercapto-5-methoxyphenyl)-1-methylcyclohexanecarboxamide (formula(I); R=1-methylcyclohexyl, X₁, X₃, X₄=a hydrogen atom, X₂=methoxy,Y=carbonyl, Z=a hydrogen atom

Step 8) S-(4-methoxy-2-nitrophenyl) N,N-dimethylthiocarbamate (formula(VIII); R₁₁, R₁₂=methyl, X₁, X₃, X₄=a hydrogen atom, X₂=methoxy).

A dimethylformamide solution (20 ml) containing 4-methoxy-2-nitrophenol(4.00 g) was added dropwise to a suspension of sodium hydride (1.04 g)in dimethylformamide (40 ml) at 0° C. under stirring. After completionof addition, the mixture was stirred for 30 minutes at room temperature,dimethylthiocarbamoyl chloride (3.65 g) was further added thereto andthe solution was stirred for 1 hour at 80° C. After allowing thesolution to cool, water was added thereto and the solution was extractedwith ethyl acetate. The organic layer was washed with 5% hydrochloricacid, water, and saturated brine, and was dried over anhydrous sodiumsulfate. The solution was concentrated and ether-hexane was added to theresidue thus obtained. A deposited solid was collected by filtration toobtain a yellow solid (5.11 g, yield: 84%). Then, phenyl ether (10 ml)was added to the resulting product (3.50 g). After stirring for 1 hourat 210° C., the solution was allowed to cool. The resulting solution waspurified by silica gel column chromatography (a developing solvent;hexane:ethyl acetate=7:1-3:2) to obtain the desired compound (3.35 g,yield: 96%).

Step 9) S-[2-(1-methylcyclohexanecarbonylamino)-4-methoxyphenyl)N,N-dimethylthiocarbamate (formula (IX); R=1-methylcyclohexyl, R₁₁,R,₁₂=methyl, X₁, X₃, X₄=a hydrogen atom, X₃=methoxy, Y=carbonyl).

An ethyl acetate solution (75 ml) containing the compound (2.00 g)obtained in the above step 8) and SnCl₂.2H₂0 (3.65 g) was stirred atroom temperature overnight. Ethyl acetate (100 ml) was added to thesolution and, then, an aqueous sodium hydroxide was further addedthereto. Magnesium sulfate was added to the mixture and solid depositedwas filtered off. The filtrate was concentrated to obtainS-(2-amino-4-methoxyphenyl) N,N-dimethylthiocarbamate (1.64 g, yield:93%). After addition of pyridine (2.9 ml) and chloroform (20 ml)thereto, 1-methylcyclohexanecarbonyl chloride (1.39 g) was addeddropwise thereto at room temperature under stirring, followed bystirring for 1 hour. After distilling off the solvent, water was addedand the solution was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and was dried over anhydroussodium sulfate. The residue obtained by concentration was purified bysilica gel column chromatography (a developing solvent; hexane:ethylacetate=3:1) to obtain the desired compound (2.41 g, yield: 95%).

Step 10) The compound obtained in the above step 9) (250 mg) was addedto a solution containing potassium hydroxide (140 mg) and methanol (1.5ml)-tetrahydrofuran (0.5 ml), and the mixture was refluxed for 30minutes under heating. After allowing to cool, water was added and theaqueous layer was washed with hexane. The solution was acidified byadding an aqueous potassium hydrogensulfate, followed by extraction withethyl acetate. The organic layer was washed with water and a saturatedbrine, and was dried over anhydrous sodium sulfate. The residue obtainedafter concentration was purified by column chromatography (a developingsolvent; hexane:ethyl acetate=40:1) to obtain the desired compound (104mg, yield: 52%).

EXAMPLES 20-24

The compounds shown in Table 9 were obtained in the same manner as inExample 19.

TABLE 9 Example Compound m.p. (° C.) ¹H NMR(CDCl₃300MHz) 19

Oil 8.75(1H, brs) 8.19(1H, d, J=2.7Hz) 7.42(1H, d, J=8.4Hz) 6.57(1H, dd,J=2.7, 8.4Hz) 3.82(3H, s) 2.91(1H, s) 2.05-2.15(2H, m) 1.25-1.70(8H, m)1.30(3H, s) 20

103-107 8.59(1H, s) 8.34(1H, brs) 7.61(1H, s) 3.10(1H, s) 2.00-2.20(2H,m) 1.10-1.75(13H, m) 0.86(6H, d, J=6.6Hz) 21

56-57 8.75(1H, s) 8.55(1H, brs) 7.60(1H, s) 3.09(1H, s) 1.10-2.20(13H,m) 0.87(6H, d, J=6.6Hz) 22

83.5-85.5 8.44(1H, brs) 8.22(1H, d, J=1.5Hz) 7.33(1H, d, J=7.8Hz)6.83(1H, dd, J=1.5, 7.8Hz) 2.96(1H, s) 2.34(3H, s) 1.10-2.20(15H, m)0.85(6H, d, J=6.6Hz) 23

85-87 8.50(1H, brs) 8.17(1H, dd, J=1.5, 8.4Hz) 7.21(1H, t, J=8.4Hz)7.00(1H, dd, J=1.5, 8.4Hz) 2.73(1H, brs) 2.47(3H, s) 2.05-2.20(2H, m)1.10-1.75(13H, m) 0.86(6H, d, J=6.6Hz) 24

71-72 8.20(1H, brs) 8.12(1H, d, J=8.4Hz) 7.31(1H, s) 7.10(1H, d,J=8.4Hz) 3.05(1H, s) 2.28(3H, s) 2.08-2.16(2H, m) 1.13-1.60(13H, m)0.85(6H, d, J=6.6Hz)

The compounds 19-1 through 19-9 shown in Table 10 were also obtained inthe same manner as in Example 19.

TABLE 10 No. Compound 19-1

19-2

19-3

19-4

19-5

19-6

19-7

19-8

19-9

EXAMPLE 25 Synthesis ofS-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thioacetate (formula(I); R=1-isopentylcyclohexyl, X₁, X₂, X₃, X₄=a hydrogen atom,Y=carbonyl, Z=acetyl)

Step 4) Acetyl chloride (0.17 ml) was added dropwise to a chloroformsolution (10 ml) containingN-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide (600 mg) obtainedin the same manner as in step 2) of Example 9, step 7) of Example 11, orthe step 10) of Example 19 and pyridine (0.48 ml) at room temperatureunder stirring. The solution was stirred for 1 hour. The residueobtained after concentration was purified by silica gel columnchromatography (a developing solvent; hexane:ethyl acetate=12:1) toobtain the desired compound (666 mg, yield: 98%).

EXAMPLE 26 Synthesis ofS-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]-phenyl]2-methylthiopropionate(formula (I); R=1-(2-ethylbutyl)cyclohexyl, X₁, X₂, X₃, X₄=a hydrogenatom, Y=carbonyl, Z=isobutyryl)

Step 4) Isobutyryl chloride (15.0 ml) was added dropwise to a chloroformsolution (300 ml) containingN-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide (43.72 g)obtained in Example 10 and pyridine (27.7 ml) at room temperature understirring. The solution was stirred for 1 hour. After concentration,hexane was added and the deposited solid was filtered off. The filtratewas concentrated and the resulting residue was purified by silica gelcolumn chromatography (a developing solvent; hexane:ethyl acetate=15:1)to obtain the desired compound (50.72 g, yield: 95%).

EXAMPLE 27 Synthesis ofS-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate(formula (I); R=1-isobutylcyclohexyl, X₁, X₂, X₃, X₄=a hydrogen atom,Y=carbonyl, Z=isobutyryl)

Step 4) Isobutyryl chloride (0.92 ml) was added dropwise to a chloroformsolution (25 ml) containingN-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide (2.50 g) obtainedin Example 18 and pyridine (1.8 ml) at room temperature under stirring.The solution was stirred for 1 hour. The residue obtained afterconcentration was purified by silica gel column chromatography (adeveloping solvent; hexane:ethyl acetate=15:1) to obtain the desiredcompound (2.94 g, yield: 95%).

EXAMPLE 28 Synthesis ofS-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino)phenyl]1-acetylpiperidine-4-thiocarboxylate(formula (I); R=1-(2-ethylbutyl)cyclohexyl, X₁, X₂, X₃, X₄=a hydrogenatom, Y=carbonyl, Z=1-acetyl-4-piperidinecarbonyl)

Step 4) A chloroform solution (10 ml) containingN-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide (933 mg)obtained in Example 10 and pyridine (0.5 ml)was added dropwise to achloroform solution (10 ml) containing 1-acetylisonipecotic acid (500mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (616mg), and 1-hydroxybenzotriazole (435 mg) at room temperature. Thesolution was stirred for 1 hour. After stirring, water was added and thesolution was extracted with ethyl acetate. The organic layer was washedwith a saturated brine and dried over anhydrous sodium sulfate. Theresidue obtained after concentration was purified by silica gel columnchromatography (a developing solvent; hexane:ethylacetate=4:1-chloroform:methanol=10:1) to obtain the desired compound(1.08 g, yield: 79%).

EXAMPLE 28′

The compound of Example 28 (formula (I); R=1-(2-ethylbutyl)cyclohexyl,X₁, X₂, X₃, X₄=a hydrogen atom, Y=carbonyl,Z=1-acetyl-4-piperidinecarbonyl) was synthesized using another synthesismethod.

Step 4) Triethylamine (541 ml) was added to an ethylacetate suspension(2 liters) containing 1-acetylisonipecotic acid (331 g) under a streamof argon. The solution was stirred under ice cooling. An ethyl acetatesolution (400 ml) containing ethyl chlorocarbonate (185 ml) was addeddropwise thereto and the mixture was further stirred for 100 min underspontaneous elevation of the temperature. After ice-cooling, an ethylacetate solution (2 liters) ofN-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide (618 g)obtained in Example 10 was added dropwise to the reaction solution,which was stirred further for 15 minutes under ice-cooling. Afterstirring, 1 N hydrochloric acid (1.3 liter) was added, the organic layerwas washed successively with water, an aqueous saturated sodiumbicarbonate, water, and a saturated brine, and dried over anhydroussodium sulfate. The residue obtained after concentration was dissolvedin diisopropyl ether (2.5 liter) and the solution was stirred forcrystallization to obtain a crude crystal. The crystal was furtherdissolved in diisopropyl ether (5.5 liter) under heating and thesolution was stirred for crystallization to obtain the desired compound(505 g, yield:55%).

EXAMPLES 29-65

The compounds shown in Tables 11-17 were obtained in the same manner asin Examples 25, 26, 27, 28, or 28′.

TABLE 11 Example Compound m.p. (° C.) ¹H NMR(CDCl₃300MHz) 25

54-55 8.34(1H, dd, J=1.5, 8.4Hz) 8.05(1H, brs) 7.46(1H, ddd, J=1.5, 7.8,8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz) 2.45(3H, s)2.03(2H, m) 1.10-1.61(13H, m) 0.85(6H, d, J=6.6Hz) 26

63.0-63.5 8.40(1H, dd, J=1.5, 8.4Hz) 8.12(1H, brs) 7.45(1H, ddd, J=1.5,7.8, 8.4Hz) 7.38(1H, dd, J=1.5, 7.8Hz) 7.11(1H, dt, J=1.5, 7.8Hz)2.94(2H, sept, J=6.9Hz) 1.95-2.20(2H, m) 1.15-1.75(15H, m) 1.30(6H, d,J=6.9Hz) 0.78(6H, t, J=6.9Hz) 27

63.5-65.5 8.39(1H, dd, J=1.5, 8.4Hz) 8.10(1H, brs) 7.45(1H, ddd, J=1.5,7.8, 8.4Hz) 7.38(1H, dd, J=1.5, 7.8Hz) 7.11(1H, dt, J=1.5, 7.8Hz)2.94(2H, sept, J=6.9Hz) 1.95-2.10(2H, m) 1.10-1.85(11H, m) 1.29(6H, d,J=6.9Hz) 0.87(6H, d, J=6.6Hz) 28

89.0-91.5 8.37(1H, dd, J=1.5, 8.4Hz) 8.03(1H, brs) 7.46(1H, ddd, J=1.5,7.8, 8.4Hz) 7.36(1H, dd, J=1.5, 7.8Hz) 7.11(1H, dt, J=1.5, 7.8Hz)4.58(1H, m) 3.88(1H, m) 3.18(1H, m) 2.91(1H, m) 2.82(1H, m)1.95-2.20(4H, m) 2.11(3H, s) 1.15-1.85(17H, m) 0.78(6H, t, J=6.9Hz) 29

144-145 8.52(1H, brs) 8.42(1H, dd, J=1.5, 8.1Hz) 8.34(2H, dd, J=1.8,6.9Hz) 8.00(2H, dd, J=1.8, 6.9Hz) 7.54(1H, ddd, J=1.5, 7.5, 8.1Hz)7.45(1H, dd, J=1.5, 7.5Hz) 7.23(1H, dt, J=1.5, 7.5Hz) 1.34(9H, s) 30

41-42 8.39(1H, dd, J=1.5, 8.4Hz) 8.07(1H, brs) 7.44(1H, ddd, J=1.5, 7.8,8.4Hz) 7.36(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5, 7.8Hz)1.96-2.05(2H, m) 1.15-1.65(8H, m) 1.35(9H, s) 1.22(3H, s)

TABLE 12 Example Compound m.p. (° C.) ¹H NMR(CDCl₃300MHz) 31

61-62 8.32(1H, dd, J=1.5, 8.4Hz) 7.85(1H, brs) 7.20-7.50(7H, m) 7.10(1H,dt, J=1.5, 7.8Hz) 3.94(2H, s) 1.17(9H, s) 32

78.5-79.0 8.40(1H, dd, J=1.5, 8.4Hz) 8.17(1H, brs) 8.05(2H, m) 7.66(1H,ddd, J=1.5, 7.8, 8.4Hz) 7.43-7.60(4H, m) 7.17(1H, dt, J=1.5, 7.8Hz)1.85-2.00(2H, m) 1.10-1.70(8H, m) 1.18(3H, s) 33

55-56 8.39(1H, dd, J=1.5, 8.4Hz) 8.04(1H, brs) 7.45(1H, ddd, J=1.5, 7.8,8.4Hz) 7.36(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5, 7.8Hz)2.00-2.03(2H, m) 1.10-1.60(13H, m) 1.35(9H, s) 0.85(6H, d, J=6.6Hz) 34

155-156 8.39(1H, dd, J=1.5, 8.4Hz) 7.98(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.09-7.38(7H, m) 5.85(1H, d, J=7.8Hz) 5.04(1H, dt, J=5.7,7.8Hz) 3.20(1H, dd, J=6.0, 14.1Hz) 3.11(1H, dd, J=7.5, 14.1Hz)1.97-2.10(5H, m) 1.00-1.80(13H, m) 0.81(6H, d, J=6.6Hz) 35

106-110 9.42(1H, s) 9.14(1H, d, J=5.1Hz) 8.90(1H, d, J=8.1Hz) 8.32(1H,d, J=7.8Hz) 8.12(1H, m) 7.89(1H, s) 7.58(1H, t, J=7.8Hz) 7.49(1H, d,J=7.8Hz) 7.24(1H, t, J=7.8Hz) 5.94(1H, brs) 1.89-2.03(2H, m)1.07-1.60(13H, m) 0.80(6H, d, J=6.6Hz) 36

68-69 8.35(1H, dd, J=1.5, 8.4Hz) 7.93(1H, brs) 7.50(1H, ddd, J=1.5, 7.8,8.4Hz) 7.40(1H, dd, J=1.5, 7.8Hz) 7.15(1H, dt, J=1.5, 7.8Hz) 4.28(2H, s)1.96-2.09(2H, m) 1.09-1.65(13H, m) 0.85(6H, d, J=6.6Hz)

TABLE 13 Example Compound m.p. (° C.) ¹H NMR(CDCl₃300MHz) 37

53-54 8.37(1H, dd, J=1.5, 8.4Hz) 7.98(1H, brs) 7.47(1H, ddd, J=1.5, 7.8,8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.13(1H, dt, J=1.5, 7.8Hz) 4.19(2H, s)3.58(3H, s) 1.95-2.10(2H, m) 1.05-1.65(13H, m) 0.85(6H, d, J=6.6Hz) 38

40-41 8.35(1H, dd, J=1.5, 8.4Hz) 8.06(1H, brs) 7.45(1H, ddd, J=1.5, 7.8,8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.17(1H, dt, J=1.5, 7.8Hz) 2.72(2H, q,J=7.5Hz) 1.95-2.10(2H, m) 1.10-1.60(13H, m) 1.24(3H, t, J=7.2Hz)0.85(6H, d, J=6.6Hz) 39

60.5-62.0 8.37(1H, dd, J=1.5, 8.4Hz) 7.90(1H, brs) 6.90-7.50(8H, m)4.79(2H, s) 1.00-2.00(15, m) 0.83(6H, d, J=6.6Hz) 40

51-52 8.30(1H, dd, J=1.5, 8.4Hz) 8.00(1H, brs) 7.40(1H, ddd, J=1.5, 7.8,8.4Hz) 7.33(1H, dd, J=1.5, 7.8Hz) 7.06(1H, dt, J=1.5, 7.8Hz) 2.88(1H, m)1.94-1.98(2H, m) 1.07-1.51(13H, m) 1.24(6H, d, J=7.0Hz) 0.85(6H, d,J=6.6Hz) 41

95-96 8.35(1H, dd, J=1.5, 8.4Hz) 7.87(1H, brs) 7.48(1H, ddd, J=1.5, 7.8,8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.31(2H, m) 7.14(1H, dt, J=1.5, 7.8Hz)6.93(2H, m) 4.78(2H, s) 1.90-1.94(2H, m) 1.07-1.58(13H, m) 0.83(6H, d,J=6.6Hz) 42

52-53 8.31(1H, dd, J=1.5, 8.4Hz) 8.09(1H, brs) 7.45(1H, ddd, J=1.5, 7.8,8.4Hz) 7.41(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5, 7.8Hz)1.92-2.25(3H, m) 1.00-1.75(17H, m) 0.86(6H, d, J=6.6Hz)

TABLE 14 Example Compound m.p. (° C.) ¹H NMR(CDCl₃300MHz) 43

Oil 8.36(1H, dd, J=1.5, 8.4Hz) 8.05(1H, brs) 7.44(1H, ddd, J=1.5, 7.8,8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz)2.55-2.75(1H, m) 1.95-2.10(4H, m) 1.10-1.85(21H, m) 0.85(6H, d, J=6.6Hz)44

Amorphous 8.38(1H, d, J=8.7Hz) 8.15(1H, brs) 8.04-8.08(2H, m) 7.66(1H,m) 7.48-7.55(4H, m) 7.16(1H, dt, J=1.2, 7.8Hz) 1.93-2.14(2H, m)1.07-1.51(13H, m) 0.78(6H, d, J=6.6Hz) 45

136-138 8.41(1H, dd, J=1.5, 8.4Hz) 8.01(1H, brs) 7.46(1H, ddd, J=1.5,7.8, 8.4Hz) 7.34(1H, dd, J=1.5, 7.8Hz) 7.23(1H, d, J=7.1Hz) 7.11(1H, dt,J=1.5, 7.8Hz) 5.72(1H, brs) 5.41(1H, brs) 4.69(1H, m) 1.95-2.58(6H, m)1.05-1.70(13H, m) 0.85(6H, d, J=6.6Hz) 46

91-92 8.42(1H, dd, J=1.5, 8.4Hz) 7.99(1H, brs) 7.47(1H, ddd, J=1.5, 7.8,8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz) 2.64(1H,brs) 1.90-2.10(2H, m) 1.05-1.70(13H, m) 1.54(6H, s) 0.86(6H, d, J=6.6Hz)47

144-146 9.90(3H, brs) 8.07(1H, dd, J=1.5, 8.4Hz) 7.98(1H, s) 7.42(1H,ddd, J=1.5, 7.8, 8.4Hz) 7.41(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5,7.8Hz) 1.95-2.20(2H, m) 1.10-1.85(21H, m) 0.84(6H, d, J=6.6Hz) 48

45-46 8.37(1H, dd, J=1.5, 8.4Hz) 7.93(1H, brs) 7.43(1H, ddd, J=1.5, 7.8,8.4Hz) 7.35(1H, dd, J=1.5, 7.8Hz) 7.09(1H, dt, J=1.5, 7.8Hz)2.05-2.20(2H, m) 1.45-1.75(9H, m) 1.36(9H, s) 1.10-1.25(2H, m) 0.86(6H,d, J=6.6Hz)

TABLE 15 Example Compound m.p. (° C.) ¹H NMR(CDCl₃300MHz) 49

50-51 8.33(1H, dd, J=1.5, 8.4Hz) 7.95(1H, brs) 7.46(1H, ddd, J=1.5, 7.8,8.4Hz) 7.40(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz) 2.46(3H, s)2.05-2.25(2H, m) 1.40-1.80(9H, m) 1.10-1.25(2H, m) 0.87(6H, d, J=6.6Hz)50

129-130 8.72(1H, s) 8.01(1H, brs) 7.44(1H, s) 1.90-2.10(2H, m)1.10-1.75(13H, m) 1.35(9H, s) 0.85(6H, d, J=6.6Hz) 51

66-67 8.68(1H, s) 7.88(1H, brs) 7.43(1H, s) 2.05-2.20(2H, m)1.30-1.75(9H, m) 1.35(9H, s) 1.05-1.20(2H, m) 0.86(6H, d, J=6.6Hz) 52

69-71 8.82(1H, d, J=1.5Hz) 8.16(1H, brs) 7.48(1H, d, J=8.1Hz) 7.34(1H,dd, J=1.5, 8.1Hz) 1.90-2.15(2H, m) 1.05-1.75(13H, m) 1.37(9H, s)0.86(6H, d, J=6.6Hz) 53

Oil 8.35(1H, dd, J=1.5, 8.4Hz) 8.05(1H, brs) 7.47(1H, ddd, J=1.5, 7.8,8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.13(1H, dt, J=1.5, 7.8Hz) 2.74(2H, t,J=6.9Hz) 2.40(2H, t, J=6.9Hz) 1.90-2.10(2H, m) 1.05-1.90(17H, m)0.86(6H, d, J=6.6Hz) 54

Oil 8.39(1H, dd, J=1.5, 8.4Hz) 8.27(1H, brs) 7.52(1H, dd, J=1.5, 7.8Hz)7.47(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.11(1H, dt, J=1.5, 7.8Hz) 3.84(3H, s)2.00-2.10(2H, m) 1.10-1.65(13H, m) 0.85(6H, d, J=6.6Hz)

TABLE 16 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300 MHz) 55

Oil 8.44(1H, dd, J=1.5, 8.4Hz) 8.29(1H, brs) 7.35-7.55(7H, m) 7.13(1H,dt, J=1.5, 7.8Hz) 1.95-2.15(2H, m) 1.25-1.70(8H, m) 1.27(3H, s) 56

40-41 8.58(1H, brs) 8.42(1H, dd, J=1.5, 7.7Hz) 7.61(1H, dd, J=1.5,7.7Hz) 7.53(1H, dt, J=1.5, 7.7Hz) 7.10-7.35(7H, m) 2.03-2.09(2H, m)1.09-1.59(13H, m) 0.78(6H, d, J=6.6Hz) 57

103 8.80(1H, d, J=1.5Hz) 8.16(1H, brs) 7.48(1H, d, J=8.1Hz) 7.35(1H, dd,J=1.5, 7.8Hz) 1.37(9H, s) 1.30(9H, s) 58

Oil 8.22(1H, d, J=1.5Hz) 8.03(1H, brs) 7.26(1H, d, J=7.8Hz) 6.93(1H, dd,J=1.5, 7.8Hz) 2.43(3H, s) 2.38(3H, s) 1.10-2.10(15H, m) 0.85(6H, d,J=6.6Hz) 59

76.5-79.0 8.38(1H, dd, J=1.5, 8.4Hz) 8.13(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.40(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz)2.46(3H, s) 2.00-2.15(2H, m) 1.15-1.70(15H, m) 0.79(6H, t, J=6.9Hz) 60

64.5-66.5 8.42(1H, dd, J=1.5, 8.4Hz) 8.11(1H, brs) 7.45(1H, ddd, J=1.5,7.8, 8.4Hz) 7.36(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5, 7.8Hz)1.95-2.15(2H, m) 1.10-1.75(15H, m) 1.36(9H, s) 0.79(6H, t, J=6.9Hz)

TABLE 17 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300 MHz) 61

67.5-69.5 8.40(1H, dd, J=1.5, 8.4Hz) 8.06(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.13(1H, dt, J=1.5, 7.8Hz)4.20(2H, s) 3.59(3H, s) 1.95-2.15(2H, m) 1.10-1.75(15H, m) 0.79(6H, t,J=6.9Hz) 62

68.0-70.0 8.44(1H, dd, 1.5, 8.4Hz) 8.06(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz)2.61(1H, s) 2.00-2.15(2H, m) 1.15-1.75(15H, m) 1.54(6H, s) 0.78(6H, t,J=6.9Hz) 63

62.0-63.0 8.39(1H, dd, J=1.5, 8.4Hz) 7.95(1H, brs) 7.48(1H, ddd, J=1.5,7.8, 8.4Hz) 7.38(1H, dd, J=1.5, 7.8Hz) 7.32(2H, m) 7.14(1H, dt, J=1.5,7.8Hz) 6.94(2H, m) 4.78(2H, s) 1.85-2.05(2H, m) 1.15-1.70(15H, m)0.77(6H, t, J=6.9Hz) 64

61.0-65.0 8.40(1H, dd, J=1.5, 8.4Hz) 7.92(1H, brs) 7.49(1H, ddd, J=1.5,7.8, 8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.33(2H, m) 7.15(1H, dt, J=1.5,7.8Hz) 6.96(2H, m) 4.80(2H, s) 1.85-2.00(2H, m) 1.20-1.80(11H, m)0.86(6H, d, J=6.6Hz) 65

61.0-64.0 8.38(1H, dd, J=1.5, 8.4Hz) 8.02(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz)4.59(1H, m) 3.88(1H, m) 3.17(1H, m) 2.92(1H, m) 2.78(1H, m)1.90-2.20(4H, m) 2.11(3H, s) 1.20-1.85(13H, m) 0.87(6H, d, J=6.6Hz)

The compounds 25-1 through 25-109 shown in Tables 18 through 27 wereobtained in the same manner as in Examples 25 through 28.

TABLE 18 No. Compound 25-1

25-2

25-3

25-4

25-5

25-6

25-7

25-8

25-9

25-10

25-11

25-12

TABLE 19 No. Compound 25-13

25-14

25-15

25-16

25-17

25-18

25-19

25-20

25-21

25-22

25-23

25-24

TABLE 20 No. Compound 25-25

25-26

25-27

25-28

25-29

25-30

25-31

25-32

25-33

25-34

25-35

25-36

TABLE 21 No. Compound 25-37

25-38

25-39

25-40

25-41

25-42

25-43

25-44

25-45

25-46

25-47

25-48

TABLE 22 No. Compound 25-49

25-50

25-51

25-52

25-53

25-54

25-55

25-56

25-57

25-58

25-59

25-60

TABLE 23 No. Compound 25-61

25-62

25-63

25-64

25-65

25-66

25-67

25-68

25-69

25-70

25-71

25-72

TABLE 24 No. Compound 25-73

25-74

25-75

25-76

25-77

25-78

25-79

25-80

25-81

25-82

25-83

25-84

TABLE 25 No. Compound 25-85

25-86

25-87

25-88

25-89

25-90

25-91

25-92

25-93

25-94

25-95

25-96

TABLE 26 No. Compound 25-97

25-98

25-99

25-100

25-101

25-102

25-103

25-104

25-105

25-106

25-107

25-108

TABLE 27 No. Compound 25-109

EXAMPLE 66 Synthesis ofS-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate(formula (I); R=1-isopropylcyclohexyl, X₁, X₄=a hydrogen atom, X₂, X₃=achlorine atom, Y=carbonyl, Z=pivaloyl)

Step 4) A tetrahydrofuran (0.5 ml)-methanol (1 ml) solution containingS-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)phenyl]N,N-dimethylthiocarbamate(86 mg) obtained in the same manner as in the step 9) of Example 19 andpotassium hydroxide (50 mg) was refluxed for 30 minutes under heating.After the solution was allowed to cool, water was added and the aqueouslayer was washed with hexane. Then, the aqueous layer was acidified withpotassium hydrogensulfate, and was extracted with chloroform (10 ml).Pyridine (90 μl) was added to the resulting extract, and pivaloylchloride (41 μl) was further added to the extract at room temperatureunder stirring. The solution was stirred for 1 hour. Afterconcentration, the residue was purified by silica gel columnchromatography (a developing solvent; hexane:ethyl acetate=20:1) toobtain the desired compound (24 mg, yield: 27%).

EXAMPLES 67-81 The compounds shown in Tables 28-30 were obtained in thesame manner as in Example 66.

TABLE 28 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300 MHz) 66

92-92 8.75(1H, s) 8.01(1H, brs) 7.44(1H, s) 1.95-2.10(2H, m)1.10-1.75(9H, m) 1.34(9H, s) 0.91(6H, d, J=6.6Hz) 67

95-96 8.73(1H, s) 8.10(1H, brs) 7.44(1H, s) 1.85-2.00(2H, m)1.10-1.70(8H, m) 1.34(9H, s) 0.89(6H, m) 0.35-0.47(4H, m) 68

109-110 8.67(1H, s) 7.61(1H, brs) 7.44(1H, s) 2.06(1H, quint, J=7.2Hz)0.85-1.85(11H, m) 1.36(9H, s) 1.18(3H, d, J=6.6Hz) 69

109-110 8.71(1H, s) 8.01(1H, brs) 7.44(1H, s) 1.95-2.05(2H, m)1.05-1.70(18H, m) 1.35(9H, s) 0.84(3H, t, J=6.7Hz) 0.84(6H, d, J=6.6Hz)70

116-117 8.76(1H, s) 8.11(1H, brs) 7.44(1H, s) 2.02-2.15(2H, m)1.20-1.65(8H, m) 1.34(9H, s) 0.55-0.65(1H, m) 0.35-0.45(2H, m)0.01-0.02(4H, m) 71

111-112 8.70(1H, s) 8.03(1H, brs) 7.44(1H, s) 1.90-2.10(2H, m)0.75-1.75(21H, m) 1.36(9H, s)

TABLE 29 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300 MHz) 72

101-102 8.70(1H, s) 7.92(1H, brs) 7.43(1H, s) 2.00-2.15(2H, m)1.30-1.65(13H, m) 1.35(9H, s) 1.05-1.15(2H, m) 0.85(6H, d, J=6.6Hz) 73

53-54 8.70(1H, s) 7.68(1H, brs) 7.44(1H, s) 2.35-2.50(2H, m)1.25-2.05(7H, m) 1.34(9H, s) 1.05-1.15(2H, m) 0.88(6H, d, J=6.6Hz) 74

93.0-93.5 9.39(1H, d, J=2.4Hz) 8.20(1H, brs) 7.93(1H, dd, J=2.4, 8.4Hz)7.53(1H, d, J=8.4Hz) 1.95-2.15(2H, m) 1.00-1.75(13H, m) 1.37(9H, s)0.85(6H, d, J=6.6Hz) 75

103-104 8.85(1H, d, J=1.5Hz) 8.14(1H, brs) 7.46(1H, d, J=7.8Hz) 7.35(1H,dd, J=1.5, 7.8Hz) 1.95-2.15(2H, m) 1.00-1.75(13H, m) 1.36(9H, s)0.85(6H, d, J=6.6Hz) 76

77-78 8.57(1H, d, J=2.7Hz) 8.06(1H, brs) 7.27(1H, d, J=7.8Hz) 7.08(1H,dd, J=2.7, 7.8Hz) 1.95-2.10(2H, m) 1.05-1.65(13H, m) 1.34(9H, s)0.84(6H, d, J=6.6Hz) 77

80-82 8.38(1H, d, J=8.7Hz) 7.99(1H, brs) 7.40(1H, dd, J=2.7, 8.7Hz)7.35(1H, d, J=2.7Hz) 1.90-2.05(2H, m) 1.05-1.65(13H, m) 1.35(9H, s)0.84(6H, d, J=6.6Hz)

TABLE 30 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300 MHz) 78

76-77 8.20(1H, d, J=2.7Hz) 8.09(1H, brs) 7.22(1H, d, J=8.4Hz) 6.66(1H,dd, J=2.7, 8.4Hz) 3.85(3H, s) 1.95-2.05(2H, m) 1.05-1.65(13H, m)1.34(9H, s) 0.84(6H, d, J=6.6Hz) 79

55-56 8.34(1H, dd, J=3.0, 11.4Hz) 8.11(1H, brs) 7.31(1H, dd, J=6.3,8.4Hz) 6.81(1H, ddd, J=3.0, 8.4, 11.4Hz) 1.95-2.15(2H, m) 1.05-1.65(13H,m) 1.34(9H, s) 0.84(6H, d, J=6.6Hz) 80

97-98 8.44(1H, dd, J=8.1, 12.9Hz) 7.98(1H, brs) 7.19(1H, dd, J=8.4,9.6Hz) 1.95-2.05(2H, m) 1.05-1.65(13H, m) 11.34(9H, s) 0.84(6H, d,J=6.6Hz) 81

94-95 8.29-8.35(1H, m) 7.90(1H, brs) 7.09-7.19(2H, m) 1.92-2.06(2H, m)1.09-1.55(13H, m) 1.35(9H, s) 0.85(6H, d, J=6.6Hz)

The compounds 66-1 through 66-53 shown in Tables 31 through 35 were alsoobtained in the same manner as in Example 66.

TABLE 31 No. Compound 66-1

66-2

66-3

66-4

66-5

66-6

66-7

66-8

66-9

66-10

66-11

66-12

TABLE 32 No. Compound 66-13

66-14

66-15

66-16

66-17

66-18

66-19

66-20

66-21

66-22

66-23

66-24

TABLE 33 No. Compound 66-25

66-26

66-27

66-28

66-29

66-30

66-31

66-32

66-33

66-34

66-35

66-36

TABLE 34 No. Compound 66-37

66-38

66-39

66-40

66-41

66-42

66-43

66-44

66-45

66-46

66-47

66-48

TABLE 35 No. Compound 66-49

66-50

66-51

66-52

66-53

82-1

EXAMPLE 82 Synthesis ofbis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]disulfide(formula (I); R=1-isopentylcyclohexyl, X₁, X₄=a hydrogen atom, X₂, X₃=achlorine atom, Y=carbonyl,Z=4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenylthio)

Step 10)N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide(formula (III-2); R=1-isopentylcyclohexyl, X₁, X₄ =a hydrogen atom, X₂,X₃=a chlorine atom, Y=carbonyl)

A tetrahydrofuran (2 ml)-methanol (1 ml) solution containingS-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]N,N-dimethylthiocarbamate(400 mg) obtained in the same manner as in step 9 of Example 19 andpotassium hydroxide (180 mg) was refluxed for 2 hours under heating andthe resulting mixture was allowed to cool. After adding water thereto,the aqueous layer was washed with hexane, was acidified with a saturatedaqueous potassium hydrogensulfate, and was extracted with chloroform.The organic layer was washed with water and a saturated brine, and driedover anhydrous sodium sulfate. After removing anhydrous sodium sulfateby filtration, the organic solvent was distilled off under reducedpressure to obtain the crude compound.

Step 3) A dimethyl sulfoxide solution (5 ml) of the crude productobtained in the above step 10) was stirred for 2 hours at 130° C. andthe mixture was allowed to cool. Water was added to the solution, whichwas extracted with chloroform. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Theresidue obtained after concentration was purified by silica gel columnchromatography (a developing solvent; hexane:ethyl acetate=30:1) toobtain the compound (200 mg, yield: 60%).

TABLE 36 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300 MHz) 82

Amorphous 8.78(2H, s) 8.38(2H, brs) 7.24(2H, s) 1.80-2.00(4H, m)1.00-1.75(26, m) 0.86(12H, d, J=6.6Hz)

The compound 82-1 shown in Table 35 was obtained in the same manner asin Example 82.

EXAMPLE 83 Synthesis of2-tetrahydrofurylmethyl2-(1-isopentylcyclohexanecarbonylamino)phenyldisulfide (formula (I); R=1-isopentylcyclohexyl, X₁, X₂, X₃, X₄=ahydrogen atom, Y=carbonyl, Z=2-tetrahydrofurfurylmethylthio)

Step 5) An ethanol (6 ml)-water (6 ml) solution containingtetrahydrofurfuryl chloride (3.0 g) and sodium thiosulfate (4.13 g) wasrefluxed for 17 hours under heating and the mixture was allowed to cool.Ethanol was removed under reduced pressure and an aqueous solution ofBunte salt was obtained. An aqueous solution (1 ml) ofN-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide (380 mg) obtainedas in Example 11 and sodium hydroxide (50 mg) was added dropwise to thesolution at 0° C. and the solution was stirred for 1.5 hour. Afteraddition of ether, the organic layer was successively washed with anaqueous sodium hydroxide, water, and a saturated brine, and dried overanhydrous sodium sulfate. The residue obtained by concentration underreduced pressure was purified by silica gel column chromatography (adeveloping solvent: hexane:ethyl acetate=8:1) to obtain the desiredcompound (128 mg, yield: 24%).

EXAMPLE 84 Synthesis of phenyl 2-pivaloylaminophenyl disulfide (formula(I); R=t-butyl, X₁, X₂, X₃, X₄=a hydrogen atom, Y=carbonyl,Z=phenylthio)

Step 5′) Trimethylsilane-imidazole (202 mg) was added to a carbontetrachloride solution (5 ml) containing thiophenol (159 mg). Thesolution was stirred for 2 hours at room temperature. The depositedimidazole was filtered off to obtain a solution.

Then, sulfuryl chloride (97 mg) and triethylamine (1 drop) weresuccessively added to a carbon tetrachloride solution (5 ml) containingbis-[2-(pivaloylamino)phenyl]disulfide (300 mg) obtained as in the step1 of Example 1 at 0° C. The solution was stirred for 1.5 hour at thesame temperature and was added dropwise to the above solution cooled inan ice-salt bath and the mixture was continuously stirred for 2.5 hour.After completion of the reaction, water was added and the solution wasextracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure and the resulting residue was purified by silicagel column chromatography (a developing solvent; hexane:ethylacetate=12:1) to obtain the desired compound (337 mg, yield: 74%).

TABLE 37 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300 MHz) 83

Oil 8.53(1H, brs) 8.44(1H, dd, J=1.5, 8.4Hz) 7.58(1H, dd, J=1.5, 7.8Hz)7.40(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.04(1H, dt, J=1.5, 7.8Hz) # 4.14(2H,quint, J=6.6Hz) 3.86(1H, dt, J=8.4, 6.6Hz) 3.77(1H, dt, J=8.4, 6.6Hz)2.96(1H, dd, J=6.6, 13.2Hz) 2.84(1H, dd, J=6.6, 13.2Hz) 1.80-2.20(5H, m)1.10-1.75(14H, m) 0.86(6H, d, J=6.6Hz) 84

Oil 8.51(1H, brs) 8.40(1H, dd, J=1.5, 8.4Hz) 7.20-7.50(7H, m) 6.97(1H,dt, J=1.5, 7.8Hz) 1.30(9H, s)

In the following, the results of the test for the CETP activityinhibitory effect of the compounds of the present invention are shown.

[Test Examples]

(1) Preparation of Donor Lipoprotein

Potassium bromide (KBr) was added to the plasma of healthy subjects (40ml) to adjust specific gravity to d=1.125 g/ml. Density gradientcentrifugation (227,000×g, 4° C., 17 hours) was conducted to obtain afraction with specific gravity d>1.125 g/ml (HDL₃ fraction). Thefraction thus obtained was dialyzed against a PBS solution [10 mMNa₂HPO₄/10 mM NaH₂PO₄/0.15 M NaCl/1 mM EDTA (pH 7.4)]. Then,tritium-labeled cholesterol (10 nM) (50.3 Ci/mM) was dissolved in 95%ethanol and added gradually to the above HDL₃ fraction under stirring.The solution was incubated for 18 hours at 37° C. [Tritium-labeledcholesterol was esterified by this procedure by the action oflecithin:cholesterol acyltransferase (LCAT) present on the surface ofHDL₃ and taken up into the interior of HDL₃ as tritium-labeledcholesterylester ([³H]CE)]. After incubation, KBr was added and specificgravity was adjusted to d=1.21 g/ml. Density gradient centrifugation(227,000×g, 4° C., 17 hours) was conducted and the fraction with d<1.21g/ml was harvested. The fraction thus obtained was dialyzed against theabove PBS solution to obtain HDL₃ that took up [³H] CE ([³H]CE-HDL₃,specific gravity: 1.125<d <1.21, specific activity: 101,000 dpm/nM),which served as donor lipoprotein.

(2) Preparation of Acceptor Lipoprotein

Physiological saline (specific gravity d=1.006 g/ml) was layered uponthe plasma of healthy subjects (100 ml). Density gradient centrifugation(227,000×g, 4° C., 4 hours) was conducted and the fraction with specificgravity d>1.006 g/ml was harvested. KBr was added to the fraction thusobtained to adjust specific gravity to d=1.063 g/ml and density gradientcentrifugation (227,000×g, 4° C., 20 hours) was conducted to harvest thefraction with specific gravity d>1.063 g/ml. The thus-obtained fractionwas dialyzed against the above PBS solution to obtain fractionscontaining IDL and LDL (specific gravity: 1.006<d <1.063), which servedas acceptor lipoprotein.

Test Example 1

In vitro CETP Activity Inhibitory Effect in Whole Plasma

Plasma containing [³H] CE-HDL₃ (600,000 dpm/ml) was prepared by addingdonor lipoprotein obtained in the above (1) to plasma from healthysubjects. A sample solution was prepared using a 1:1 solution ofN-methylpyrrolidone and polyethyleneglycol 400 as a solvent. The samplesolution or the solvent alone (2 μl) and the plasma containing[³H]CE-HDL₃ (100 μl) were added to microtubes and incubated for 4 hoursat 37° C. or 4° C. After ice cooling, a TBS solution [20 mMTris/0.15 MNaCl (pH 7.4)] containing 0.15 M magnesium chloride and 0.3% dextransulfate (100 μl) were added to each microtube and mixed well. Afterallowing the microtubes to stand at 4° C. for 30 minutes, centrifugation(8,000 rpm, 4° C., 10 minutes) was conducted and the radioactivity ofthe resulting supernatant (HDL fraction) was determined with ascintillation counter. The difference between the values obtained afterincubation at 4° C. and 37° C. with the solvent alone was regarded asCETP activity and a decrease (%) of the measured values produced by thesamples was regarded as inhibition rate (%) of CETP activity. Based onthe inhibition rate (%) of CETP activity, IC₅₀ value of each sample wascalculated.

The results are shown in Tables 38-48.

Test Example 2

Ex vivo CETP Activity Inhibitory Effect of Plasma from Transgenic Mice

Samples were suspended in a 0.5% methylcellulose solution andadministered orally using a plastic probe to transgenic mice havingintroduced human CETP gene (hereafter referred to as mice; preparedusing the method described in Japanese Patent Application No. Hei8-130660), which had been fasted overnight. Blood was collected beforeadministration, and 6 hours after administration CETP activity in theplasma was determined using the following method.

Donor lipoprotein ([³H]CE-HDL₃, containing 0.21 μg cholesterol) obtainedin the above (1), acceptor lipoprotein obtained in the above (2)(containing 21 μg of cholesterol), and 0.9 μl of mice plasma were addedto microtubes. A total volume was adjusted to 600 μl/tube with a TBSsolution [10 mM Tris/0.15 M NaCl (pH 7.4)]. The microtubes wereincubated for 15 hours at 37° C. or 4° C. Then, an ice-cooled TBSsolution (400 μl/tube) and a 0.3% dextran sulfate solution (100 μl/tube)containing 0.15 M magnesium chloride were added to the microtubes andmixed well. After allowing the microtubes to stand for 30 minutes at 4°C., centrifugation (8,000 rpm, 4° C., 10 minutes) was carried out andradioactivity of the resulting supernatant (HDL fraction) was determinedwith a scintillation counter. The difference between measured valuesobtained by incubating plasma of individual mice at 4° C. and 37° C.before administration of the samples were regarded as CETP activity anda decrease (%) of measured values after administration of samples wasregarded as inhibition rate (%) of CETP activity.

The results are shown in Tables 38-48.

TABLE 38 CETP activity inhibition in CETP activity inhibitory rate inplasma from transgenic mouse (%) whole plasma 300 Example IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. mg/kg, p.o. 1 20 3 101 4 1755 3 6 5 7 2 8 3 25 9 99 11 5 27 45 57 12 17 13 5 14 8 9 15 12 16 8 17 818 6 19 179 20 16 21 9 22 56 22 44

TABLE 39 CETP activity inhibition in CETP activity inhibitory rate inplasma from transgenic mouse (%) whole plasma 300 Example IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. mg/kg, p.o. 23 18 24 29 29 2511 19 45 52 26 7 44 27 7 31 28 6 36 30 72 31 32 32 32 33 61 23 39 52 5534 9 4 35 4 36 16 19 37 7 18 42 47 38 6 15 40 39 11 17 41 40 23 20 48 6441 7 27 42 42 9 31 38 43 49

TABLE 40 CETP activity inhibition in CETP activity inhibitory rate inplasma from transgenic mouse (%) whole plasma 300 Example IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. mg/kg, p.o. 44 23 45 7 18 3646 5 22 48 47 6 31 48 49 31 50 49 6 29 50 2 51 16 52 8 8 53 8 54 12 5565 56 13 34 57 41 59 4 44 60 41 44 61 4 38 62 4 38 63 4 43 64 4 34

TABLE 41 CETP activity inhibition in CETP activity inhibitory rate inplasma from transgenic mouse (%) whole plasma 300 Example IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. mg/kg, p.o. 66 7 67 9 68 1069 6 70 4 71 4 72 74 73 37 74 14 5 75 25 1 76 18 4 77 17 1 78 11 79 6014 26 80 6 12 81 21 10 82 7 83 5 84 158

TABLE 42 CETP activity inhibition in whole plasma CETP activityinhibitory rate in plasma from transgenic mouse (%) No. IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. 300 mg/kg, p.o. 1-1 41 1-2 251-6 22 1-7 24 1-8 21 1-12 12 1-13 18 19-1 19 19-2 33 19-5 17 19-6 1825-4 32 25-7 46 25-8 25 25-12 33 25-13 28 25-14 30 25-16 41 25-17 2325-18 19

TABLE 43 CETP activity inhibition in whole plasma CETP activityinhibitory rate in plasma from transgenic mouse (%) No. IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. 300 mg/kg, p.o. 25-19 2225-20 48 25-21 28 25-22 27 25-23 25 25-25 24 25-26 22 25-27 21 25-28 2125-30 21 25-31 21 25-32 20 25-33 18 25-34 21 25-35 27 25-36 30 25-37 2425-38 20 25-39 22 25-40 23

TABLE 44 CETP activity inhibition in whole plasma CETP activityinhibitory rate in plasma from transgenic mouse (%) No. IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. 300 mg/kg, p.o. 25-42 2225-44 9 25-45 13 21 25-46 9 35 25-47 29 25-48 23 25-49 21 16 25-52 68 1940 25-53 7 26 25-54 6 25-55 10 25-56 7 24 25-57 7 18 46 25-59 8 20 3725-60 5 25-61 5 28 25-63 21 25 25-64 20 25-65 9

TABLE 45 CETP activity inhibition in whole plasma CETP activityinhibitory rate in plasma from transgenic mouse (%) No. IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. 300 mg/kg, p.o. 25-66 3525-67 40 25-72 27 25-76 36 25-77 7 25-78 11 25-79 6 25-80 5 25-81 1425-82 17 25-83 18 25-84 10 17 25-85 7 25-86 10 25-87 6 25-91 22 25-92 1925-93 22 25-94 18 25-95 18

TABLE 46 CETP activity inhibition in whole plasma CETP activityinhibitory rate in plasma from transgenic mouse (%) No. IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. 300 mg/kg, p.o. 25-96 8 25-979 19 25-98 8 25-99 6 25-100 16 25 25-101 7 8 25-102 8 9 25-103 12 25-1049 25-105 6 14 25-106 10 29 25-107 11 22 25-108 7 8 66-3 24 66-4 28 66-99 66-10 23 66-11 22 66-12 17 66-14 11

TABLE 47 CETP activity inhibition in whole plasma CETP activityinhibitory rate in plasma from transgenic mouse (%) No. IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. 300 mg/kg, p.o. 66-16 8 66-1718 66-18 11 66-21 41 66-22 19 66-23 13 66-24 12 66-25 19 66-26 8 66-27 966-28 18 66-29 7 66-30 19 66-31 27 66-32 22 66-33 19 66-34 22 66-38 2666-40 42 66-41 25

TABLE 48 CETP activity inhibition in whole plasma CETP activityinhibitory rate in plasma from transgenic mouse (%) No. IC₅₀ (μM) 10mg/kg, p.o. 30 mg/kg, p.o. 100 mg/kg, p.o. 300 mg/kg, p.o. 66-42 1066-43 23 66-46 35 66-48 11 66-49 40 66-51 45 66-52 46 66-53 15 82-1 5

Industrial Applicability

The above test results reveal that the compounds (I) of the presentinvention have an excellent CETP activity inhibitory effect. Thus, thecompounds can reduce IDL, VLDL, and LDL, which aggravateatherosclerosis, and increase HDL that acts inhibitory thereto, and,therefore, are useful as a conventionally unknown, new type of apreventive or therapeutic agent for hyperlipidemia. The compound is alsouseful as a preventive or therapeutic agent for atheroscleroticdiseases.

What is claimed is:
 1. A compound represented by the formula (I-2):

wherein R′ represents a substituted or unsubstituted C₃₋₁₀ cycloalkylgroup or a substituted or unsubstituted C₅₋₈ cycloalkenyl group; each ofX₁, X₂, X₃, and X₄ may be the same or different and represents ahydrogen atom; a halogen atom; a C₁₋₄ alkyl group; a halo-C₁₋₄ alkylgroup; a C₁₋₄ alkoxy group; a cyano group; a nitro group; an acyl group;or an aryl group; and Z₁′ represents a hydrogen atom; —Y₁R₁, wherein Y₁represents —CO— or —CS—, and R₁ represents a substituted orunsubstituted straight chain or branched C₁₋₁₀ alkyl group; a C₁₋₄alkoxy group; a C₁₋₄ alkylthio group; a substituted or unsubstitutedamino group; a substituted or unsubstituted ureido group; a substitutedor unsubstituted C₃₋₁₀ cycloalkyl group; a substituted or unsubstitutedC₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group; a substituted or unsubstituted arylgroup; a substituted or unsubstituted aralkyl group; a substituted orunsubstituted arylalkenyl group; a substituted or unsubstituted arylthiogroup; a substituted or unsubstituted 5- or 6-membered heterocyclicgroup having 1-3 nitrogen, oxygen, or sulfur atoms; or a substituted orunsubstituted 5- or 6-membered heteroarylalkyl group, or —S—R₂, whereinR₂ represents a substituted or unsubstituted C₁₋₄ alkyl group or asubstituted or unsubstituted aryl group, or a prodrug compound, apharmaceutically acceptable salt, a hydrate, or a solvate thereof.
 2. Acompound as claimed in claim 1, which is represented by the formula(III):

wherein R′, X₁, X₂, X₃, and X₄, are the same as recited in claim 1, or aprodrug compound, a pharmaceutically acceptable salt, a hydrate, or asolvate thereof.
 3. A compound as claimed in claim 1, which isrepresented by the formula (IV):

wherein R′, X₁, X₂, X₃, X₄, Y₁, and R₁, are the same as recited in claim1, or a prodrug compound, a pharmaceutically acceptable salt, a hydrate,or a solvate thereof.
 4. A compound as claimed in claim 1, which isrepresented by the formula (V):

wherein R′, X₁, X₂, X₃, X₄, and R₂, are the same as recited in claim 1,or a prodrug compound, a pharmaceutically acceptable salt, a hydrate, ora solvate thereof.
 5. A compound as claimed in claim 1, which isselected from the group consisting ofN-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;N-(2-mercaptophenyl)-1-methylcyclohexanecarboxamide;N-(2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;N-(2-mercaptophenyl)-1-isopropylcyclohexanecarboxamide;N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexane-carboxamide;N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclopentane-carboxamide;N-(2-mercapto-5-methylphenyl)-1-isopentylcyclohexane-carboxamide;N-(2-mercapto-4-methylphenyl)-1-isopentylcyclohexane-carboxamide;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thio-acetate;S-[2-(1-methylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chloro-thioacetate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxy-thioacetate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thio-propionate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclo-propanethiocarboxylate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylpropionate;2-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thio-acetate;S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-isopentylcyclopentanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[2-(1-isopentylcylohexanecarbonylamino)-4-trifluoro-methylphenyl]2,2dimethylthiopropionate;O-methylS-[2-(1-isopentylcyclohexanecarbonylamino)-phenyl]monothiocarbonate;S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyl dithiocarbonate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-pentyltyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonyl-amino)phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonyl-amino)phenyl]2,2-dimethylthiopropioate;S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylanmino)-4-nitrophenyl]2,2-dimethylthiopropionate;S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[5-chloro-2-(1-isopentylcyclohexanecarbonylanino)phenyl]2,2-dimethylthiopropionate;S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionateS-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclo-hexanethiocarboxylate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thio-benzoate;S-[2-(1-isopentylcyclohexanecarbonylamino)5-carboxythiopentanoate;S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexane-carboxamide;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;S-[2-(1-isobutylcyclohexanecarbonylamino]phenyl]2-methyl-thiopropionate;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylpropionate;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chloro-phenoxythioacetate;andS-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]1-acetylpiperidine-4-thiocarboxylate,or a prodrug compound, a pharmaceutically acceptable salt, a hydrate, ora solvate thereof.
 6. A pharmaceutical composition comprising a compoundas claimed in claim 1, or a prodrug compound, a pharmaceuticallyacceptable salt, a hydrate, or a solvate thereof and a pharmacologicallyacceptable carrier.
 7. A compound as claimed in claim 1, said compoundbeing a prodrug which which undergoes degradation under physiologicalconditions through hydrolysis or solvolysis to produce the compoundrepresented by the formula I-2.
 8. A compound as in claim 1, in which Z₁is —H.
 9. A compound as claimed in claim 1, which is represented by theformula (I-3):

wherein R″ represents a 1-substituted-C₃₋₁₀ cycloalkyl group or a1-substituted-C₅₋₈ cycloalkenyl group; X₁, X₂, X₃, and X₄, are the sameas recited in claim 1; and Z₁″ represents a hydrogen atom; —Y₁R₁,wherein Y₁, and R₁, are the same as recited in claim 1; or —S—R₂,wherein R₂ is the same as recited in claim 1, or a prodrug compound, apharmaceutically acceptable salt, a hydrate, or a solvate thereof.
 10. Acompound as claimed in claim 9, which is represented by the formula(III-1):

wherein R″, X₁, X₂, X₃, and X₄ are the same as recited in claim 9, or aprodrug compound, a pharmaceutically acceptable salt, a hydrate, or asolvate thereof.
 11. The compound as claimed in claim 10, wherein R″ isa 1-substituted C₅₋₇ cycloalkyl group or a 1-substituted C₅₋₆cycloalkenyl group.
 12. The compound as claimed in claim 11, wherein R″is cyclohexyl, cyclopentenyl, or cyclohexenyl.
 13. The compound asclaimed in claim 10, wherein R″ is substituted with a C₁₋₁₀ alkyl group,an C₂₋₁₀ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₅₋₈ cycloalkenylgroup, a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group, an aryl group, an aralkylgroup, or arylalkenyl.
 14. A compound as claimed in claim 9, which isrepresented by the formula (IV-1):

wherein R″, X₁, X₂, X₃, X₄, Y₁, and R₁ are the same as recited in claim9; or a prodrug compound, a pharmaceutically acceptable salt, a hydrate,or a solvate thereof.
 15. The compound as claimed in claim 14, whereinR″ is a 1-substituted C₅₋₇ cycloalkyl group or a 1-substituted C₅₋₆cycloalkenyl group.
 16. The compound as claimed in claim 15, wherein R″is cyclohexyl, cyclopentenyl, or cyclohexenyl.
 17. The compound asclaimed in claim 14, wherein R″ is substituted with a C₁₋₁₀ alkyl group,an C₂₋₁₀ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₅₋₈ cycloalkenylgroup, a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group, an aryl group, an aralkylgroup, or arylalkenyl.
 18. A compound as claimed in claim 9, which isrepresented by the formula (V-1):

wherein R″, X₁, X₂, X₃, X₄, and R₂, are the same as recited in claim 9,or a prodrug compound, a pharmaceutically acceptable salt, a hydrate, ora solvate thereof.
 19. The compound as claimed in claim 18, wherein R″is a 1-substituted C₅₋₇ cycloalkyl group or a 1-substituted C₅₋₆cycloalkenyl group.
 20. The compound as claimed in claim 19, wherein R″is cyclohexyl, cyclopentenyl, or cyclohexenyl.
 21. The compound asclaimed in claim 18, wherein R″ is substituted with a C₁₋₁₀ alkyl group,an C₂₋₁₀ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₅₋₈ cycloalkenylgroup, a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group, an aryl group, an aralkylgroup, or arylalkenyl.
 22. The compound as claimed in claim 9, whereinR″ is a 1-substituted C₅₋₇ cycloalkyl group or a 1-substituted C₅₋₆cycloalkenyl group.
 23. The compound as claimed in claim 22, wherein R″is cyclohexyl, cyclopentenyl, or cyclohexenyl.
 24. The compound asclaimed in claim 9, wherein R″ is substituted with a C₁₋₁₀ alkyl group,an C₂₋₁₀ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₅₋₈ cycloalkenylgroup, a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group, an aryl group, an aralkylgroup, or arylalkenyl.